@article{TsuprykovChenHocheretal.2018, author = {Tsuprykov, Oleg and Chen, Xin and Hocher, Carl-Friedrich and Skoblo, Roman and Yin, Lianghong and Hocher, Berthold}, title = {Why should we measure free 25(OH) vitamin D?}, series = {The Journal of Steroid Biochemistry and Molecular Biology}, volume = {180}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, publisher = {Elsevier}, address = {Oxford}, issn = {0960-0760}, doi = {10.1016/j.jsbmb.2017.11.014}, pages = {87 -- 104}, year = {2018}, abstract = {Vitamin D, either in its D-2 or D-3 form, is essential for normal human development during intrauterine life, kidney function and bone health. Vitamin D deficiency has also been linked to cancer development and some auto immune diseases. Given this huge impact of vitamin Don human health, it is important for daily clinical practice and clinical research to have reliable tools to judge on the vitamin D status. The major circulating form of vitamin D is 25-hydroxyvitamin D (25(OH)D), although it is not the most active metabolite, the concentrations of total 25-hydroxyvitamin D in the serum are currently routinely used in clinical practice to assess vitamin D status. In the circulation, vitamin D - like other steroid hormones - is bound tightly to a special carrier - vitamin D-binding protein (DBP). Smaller amounts are bound to blood proteins - albumin and lipoproteins. Only very tiny amounts of the total vitamin D are free and potentially biologically active. Currently used vitamin D assays do not distinguish between the three forms of vitamin D - DBP-bound vitamin D, albumin-bound vitamin D and free, biologically active vitamin D. Diseases or conditions that affect the synthesis of DBP or albumin thus have a huge impact on the amount of circulating total vitamin D. DBP and albumin are synthesized in the liver, hence all patients with an impairment of liver function have alterations in their total vitamin D blood concentrations, while free vitamin D levels remain mostly constant. Sex steroids, in particular estrogens, stimulate the synthesis of DBP. This explains why total vitamin D concentrations are higher during pregnancy as compared to nonpregnant women, while the concentrations of free vitamin D remain similar in both groups of women. The vitamin D-DBP as well as vitamin D-albumin complexes are filtered through the glomeruli and re-uptaken by megalin in the proximal tubule. Therefore, all acute and chronic kidney diseases that are characterized by a tubular damage, are associated with a loss of vitamin D-DBP complexes in the urine. Finally, the gene encoding DBP protein is highly polymorphic in different human racial groups. In the current review, we will discuss how liver function, estrogens, kidney function and the genetic background might influence total circulating vitamin D levels and will discuss what vitamin D metabolite is more appropriate to measure under these conditions: free vitamin D or total vitamin D.}, language = {en} } @article{HocherGroenSchumannetal.2012, author = {Hocher, Berthold and Groen, Hans J{\"u}rgen and Schumann, Claudia and Tsuprykov, Oleg and Seifert, Susanne and Hitzler, Walter E. and Armbruster, Franz Paul}, title = {Vitamin D status from dried capillary blood samples}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {7-8}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2012.120429}, pages = {851 -- 855}, year = {2012}, abstract = {Background: Given the huge impact of vitamin D deficiency on a broad spectrum of diseases such as rickets, osteoporosis, mineral bone disease-vascular calcification syndrome, infectious diseases, but also several types of cancer and CNS diseases, reliable and simple methods to analyze the vitamin D status are urgently needed. Methods: We developed an easy technique to determine the 25-OH vitamin D status from dried blood samples on filter paper. This allows determination of the 25-OH vitamin D status independently of venous blood taking, since only sampling of capillary blood is required for this new method. We compared the results of vitamin D measurements from venous blood of 96 healthy blood donors with those from capillary blood taken from the same patients at the same time. The capillary blood was dried on filter paper using the D-Vital ID dry-blood collection system. Results: 25-OH vitamin D concentration data from extracted dried capillary blood filters correlated very well with data obtained after direct measurement of venous blood samples of the same blood donor (R: 0.7936; p<0.0001). The correlation was linear over the whole range of 25-OH vitamin D concentrations seen in this study. A Bland-Altman plot revealed good agreement between both tests. Conclusions: The D-Vital ID dry-blood collection system showed an excellent performance as compared to the classical way of 25-OH vitamin D measurement from venous blood. This new technique will facilitate easy and reliable measurement for vitamin D status, in particular, in rural or isolated areas, developing countries, and field studies.}, language = {en} } @article{ChaykovskaHeunischvonEinemetal.2016, author = {Chaykovska, Lyubov and Heunisch, Fabian and von Einem, Gina and Alter, Markus L. and Hocher, Carl-Friedrich and Tsuprykov, Oleg and Dschietzig, Thomas and Kretschmer, Axel and Hocher, Berthold}, title = {Urinary Vitamin D Binding Protein and KIM-1 Are Potent New Biomarkers of Major Adverse Renal Events in Patients Undergoing Coronary Angiography}, series = {PLoS one}, volume = {11}, journal = {PLoS one}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0145723}, pages = {11}, year = {2016}, abstract = {Background Vitamin-D-binding protein (VDBP) is a low molecular weight protein that is filtered through the glomerulus as a 25-(OH) vitamin D 3/VDBP complex. In the normal kidney VDBP is reabsorbed and catabolized by proximal tubule epithelial cells reducing the urinary excretion to trace amounts. Acute tubular injury is expected to result in urinary VDBP loss. The purpose of our study was to explore the potential role of urinary VDBP as a biomarker of an acute renal damage. Method We included 314 patients with diabetes mellitus or mild renal impairment undergoing coronary angiography and collected blood and urine before and 24 hours after the CM application. Patients were followed for 90 days for the composite endpoint major adverse renal events (MARE: need for dialysis, doubling of serum creatinine after 90 days, unplanned emergency rehospitalization or death). Results Increased urine VDBP concentration 24 hours after contrast media exposure was predictive for dialysis need (no dialysis: 113.06 +/- 299.61ng/ml, n = 303; need for dialysis: 613.07 +/- 700.45 ng/ml, n = 11, Mean +/- SD, p < 0.001), death (no death during follow-up: 121.41 +/- 324.45 ng/ml, n = 306; death during follow-up: 522.01 +/- 521.86 ng/ml, n = 8; Mean +/- SD, p < 0.003) and MARE (no MARE: 112.08 +/- 302.00ng/ml, n = 298; MARE: 506.16 +/- 624.61 ng/ml, n = 16, Mean +/- SD, p < 0.001) during the follow-up of 90 days after contrast media exposure. Correction of urine VDBP concentrations for creatinine excretion confirmed its predictive value and was consistent with increased levels of urinary Kidney Injury Molecule1 (KIM-1) and baseline plasma creatinine in patients with above mentioned complications. The impact of urinary VDBP and KIM-1 on MARE was independent of known CIN risk factors such as anemia, preexisting renal failure, preexisting heart failure, and diabetes. Conclusions Urinary VDBP is a promising novel biomarker of major contrast induced nephropathy-associated events 90 days after contrast media exposure.}, language = {en} } @article{HeunischvonEinemAlteretal.2014, author = {Heunisch, Fabian and von Einem, Gina and Alter, Markus L. and Weist, Andreas and Dschietzig, Thomas and Kretschmer, Axel and Hocher, Berthold}, title = {Urinary ET-1 excretion after exposure to radio-contrast media in diabetic patients and patients with preexisting mild impaired renal function}, series = {Life sciences : molecular, cellular and functional basis of therapy}, volume = {118}, journal = {Life sciences : molecular, cellular and functional basis of therapy}, number = {2}, publisher = {Elsevier}, address = {Oxford}, issn = {0024-3205}, doi = {10.1016/j.lfs.2013.12.233}, pages = {440 -- 445}, year = {2014}, abstract = {Aims: Contrast media-induced nephropathy (CIN) is associated with increased morbidity and mortality. The renal endothelin system has been associated with disease progression of various acute and chronic renal diseases. However, robust data coming from adequately powered prospective clinical studies analyzing the short and long-term impacts of the renal ET system in patients with CIN are missing so far. We thus performed a prospective study addressing this topic. Main methods: We included 327 patients with diabetes or renal impairment undergoing coronary angiography. Blood and spot urine were collected before and 24 h after contrast media (CM) application. Patients were followed for 90 days for major clinical events like need for dialysis, unplanned rehospitalization or death. Key findings: The concentration of ET-1 and the urinary ET-1/creatinine ratio decreased in spot urine after CM application (ET-1 concentration: 0.91 +/- 1.23pg/ml versus 0.63 +/- 1.03pg/ml, p<0.001; ET-1/creatinine ratio: 0.14 +/- 0.23 versus 0.09 +/- 0.19, p<0.001). The urinary ET-1 concentrations in patients with CIN decreased significantly more than in patients without CIN (-0.26 +/- 1.42pg/ml vs. -0.79 +/- 1.69pg/ml, p=0.041), whereas the decrease of the urinary ET-1/creatinine ratio was not significantly different (non-CIN patients: -0.05 +/- 0.30; CIN patients: -0.11 +/- 0.21, p=0.223). Urinary ET-1 concentrations as well as the urinary ET-1/creatinine ratio were not associated with clinical events (need for dialysis, rehospitalization or death) during the 90day follow-up after contrast media exposure. However, the urinary ET-1 concentration and the urinary ET-1/creatinine ratio after CM application were higher in those patients who had a decrease of GFR of at least 25\% after 90days of follow-up. Significance: In general the ET-1 system in the kidney seems to be down-regulated after contrast media application in patients with moderate CIN risk. Major long-term complications of CIN (need for dialysis, rehospitalization or death) are not associated with the renal ET system. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.}, language = {en} } @article{ChaykovskaHeunischvonEinemetal.2018, author = {Chaykovska, Lyubov and Heunisch, Fabian and von Einem, Gina and Hocher, Carl-Friedrich and Tsuprykov, Oleg and Pavkovic, Mira and Sandner, Peter and Kretschmer, Axel and Chu, Chang and Elitok, Saban and Stasch, Johannes-Peter and Hocher, Berthold}, title = {Urinary cGMP predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus before exposure to contrast medium}, series = {PLoS one}, volume = {13}, journal = {PLoS one}, number = {4}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0195828}, pages = {13}, year = {2018}, abstract = {Background The use of iodine-based contrast agents entails the risk of contrast induced nephropathy (CIN). Radiocontrast agents elicit the third most common cause of nephropathy among hospitalized patients, accounting for 11-12\% of cases. CIN is connected with clinically significant consequences, including increased morbidity, prolonged hospitalization, increased risk of complications, potential need for dialysis, and increased mortality rate. The number of in hospital examinations using iodine-based contrast media has been significantly increasing over the last decade. In order to protect patients from possible complications of such examinations, new biomarkers are needed that are able to predict a risk of contrast-induced nephropathy. Urinary and plasma cyclic guanosine monophosphate (cGMP) concentrations are influenced by renal function. Urinary cGMP is primarily of renal cellular origin. Therefore, we assessed if urinary cGMP concentration may predict major adverse renal events (MARE) after contrast media exposure during coronary angiography. Methods Urine samples were prospectively collected from non-randomized consecutive patients with either diabetes or preexisting impaired kidney function receiving intra-arterial contrast medium (CM) for emergent or elective coronary angiography at the Charite Campus Mitte, University Hospital Berlin. Urinary cGMP concentration in spot urine was analyzed 24 hours after CM exposure. Patients were followed up over 90 days for occurrence of death, initiation of dialysis, doubling of plasma creatinine concentration or MARE. Results In total, 289 consecutive patients were included into the study. Urine cGMP/creatinine ratio 24 hours before CM exposure expressed as mean +/- SD was predictive for the need of dialysis (no dialysis: 89.77 +/- 92.85 mu M/mM, n = 277; need for dialysis: 140.3 +/- 82.90 mu M/mM, n = 12, p = 0.008), death (no death during follow-up: 90.60 +/- 92.50 mu M/mM, n = 280; death during follow-up: 169.88 +/- 81.52 mu M/mM, n = 9; p = 0.002), and the composite endpoint MARE (no MARE: 86.02 +/- 93.17 mu M/mM, n = 271; MARE: 146.64 +/- 74.68 mu M/mM, n = 18, p<0.001) during the follow-up of 90 days after contrast media application. cGMP/creatinine ratio stayed significantly increased at values exceeding 120 pM/mM in patients who developed MARE, required dialysis or died. Conclusions Urinary cGMP/creatinine ratio >= 120 mu M/mM before CM exposure is a promising biomarker for the need of dialysis and all-cause mortality 90 days after CM exposure in patients with preexisting renal impairment or diabetes.}, language = {en} } @article{HenzeEspeWanneretal.2012, author = {Henze, Andrea and Espe, Katharina M. and Wanner, Christoph and Krane, Vera and Raila, Jens and Hocher, Berthold and Schweigert, Florian J. and Drechsler, Christiane}, title = {Transthyretin predicts cardiovascular outcome in hemodialysis patients with type 2 diabetes}, series = {Diabetes care}, volume = {35}, journal = {Diabetes care}, number = {11}, publisher = {American Diabetes Association}, address = {Alexandria}, issn = {0149-5992}, doi = {10.2337/dc12-0455}, pages = {2365 -- 2372}, year = {2012}, abstract = {OBJECTIVE-BMI and albumin are commonly accepted parameters to recognize wasting in dialysis patients and are powerful predictors of morbidity and mortality. However, both parameters reveal limitations and may not cover the entire range of patients with wasting. The visceral protein transthyretin (TTR) may be helpful in overcoming the diagnostic and prognostic gap. Therefore, the aim of this study was to assess the association of TTR with morbidity and mortality in hemodialysis patients. RESEARCH DESIGN AND METHODS-The TTR concentration was determined in plasma samples of 1,177 hemodialysis patients with type 2 diabetes. Cox regression analyses were used to determine hazard ratios (HRs) for the risk of cardiovascular end points (CVEs) and mortality according to quartiles of TTR concentration for the total study cohort and the subgroups BMI >= 23 kg/m(2), albumin concentration >= 3.8 g/dL, and a combination of both. RESULTS-A low TTR concentration was associated with an increased risk for CVE for the total study cohort (HR 1.65 [95\% CI 1.27-2.14]), patients with BMI >= 23 kg/m(2) (1.70 [1.22-2.37]), albumin >= 3.8 g/dL (1.68 [1.17-2.42]), and the combination of both (1.69 [1.13-2.53]). Additionally, a low TTR concentration predicted mortality for the total study cohort (1.79 [1.43-2.24]) and patients with BMI >= 23 kg/m(2) (1.46 [1.09-1.95]). CONCLUSIONS-The current study demonstrated that TTR is a useful predictor for cardiovascular outcome and mortality in diabetic hemodialysis patients. TTR was particularly useful in patients who were not identified to be at risk by BMI or albumin status.}, language = {en} } @article{HocherSharkovskaMarketal.2013, author = {Hocher, Berthold and Sharkovska, Yuliya and Mark, Michael and Klein, Thomas and Pfab, Thiemo}, title = {The novel DPP-4 inhibitors linagliptin and BI 14361 reduce infarct size after myocardial ischemia/reperfusion in rats}, series = {International journal of cardiology}, volume = {167}, journal = {International journal of cardiology}, number = {1}, publisher = {Elsevier}, address = {Clare}, issn = {0167-5273}, doi = {10.1016/j.ijcard.2011.12.007}, pages = {87 -- 93}, year = {2013}, abstract = {Background: Dipeptidylpeptidase-4 inhibition is reported to have beneficial effects on myocardial ischemia. Mechanisms might include a reduced degradation of stromal cell-derived factor-1 alpha with subsequent increased recruitment of circulating stem cells and/or incretin receptor-dependent pathways. This study evaluated the novel xanthine-based dipeptidylpeptidase-4 inhibitors linagliptin (BI 1356) and BI 14361 in cardiac ischemia. Methods: Male Wistar rats were pretreated with linagliptin or BI 14361 and subjected to ligation of the left anterior descending coronary artery for 30 min. Results: Dipeptidylpeptidase-4 inhibition significantly reduced the infarct size after 7 days (-27.7\%, p<0.05) and 8 weeks (-18.0\%, p<0.05). There was a significantly improved maximum rate of left ventricular pressure decline (dP/dt min) in linagliptin-treated animals 8 weeks after ischemia/reperfusion. Apart from that, treatment did not improve cardiac function as determined by echocardiography and cardiac catheterization. Immunohistological staining revealed an increased number of cells positive for stromal cell-derived factor-1 alpha, CXCR-4 and CD34 within and around the infarcted area of BI 14361-treated animals. Conclusions: Linagliptin and BI 14361 are able to reduce infarct size after myocardial ischemia. The immunohistological findings support the hypothesis that dipeptidylpeptidase-4 inhibition via reduced cleavage of stromal cell-derived factor-1 alpha might lead to an enhanced recruitment of CXCR-4+ circulating progenitor cells.}, language = {en} } @article{HechtFreisevonWebskyetal.2016, author = {Hecht, Eva and Freise, Christian and von Websky, Karoline and Nasser, Hamoud and Kretzschmar, Nadja and Stawowy, Philipp and Hocher, Berthold and Querfeld, Uwe}, title = {The matrix metalloproteinases 2 and 9 initiate uraemic vascular calcifications}, series = {Nephrology, dialysis, transplantation}, volume = {31}, journal = {Nephrology, dialysis, transplantation}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {0931-0509}, doi = {10.1093/ndt/gfv321}, pages = {789 -- 797}, year = {2016}, abstract = {The matrix metalloproteinases (MMP) MMP-2 and MMP-9 are physiological regulators of vascular remodelling. Their dysregulation could contribute to vascular calcification. We examined the role of the MMP-2 and MMP-9 in uraemic vascular calcification in vivo and in vitro. The impact of pharmacological MMP inhibition on the development of media calcifications was explored in an aggressive animal model of uraemic calcification. In addition, the selective effects of addition and inhibition, respectively, of MMP-2 and MMP-9 on calcium-/phosphate-induced calcifications were studied in a murine cell line of vascular smooth muscle cells (VSMCs). High-dose calcitriol treatment of uraemic rats given a high phosphate diet induced massive calcifications, apoptosis and increased gene expressions of MMP-2, MMP-9 and of osteogenic transcription factors and proteins in aortic VSMC. The MMP inhibitor doxycycline prevented the VSMC transdifferentiation to osteoblastic cells, suppressed transcription of mediators of matrix remodelling and almost completely blocked aortic calcifications while further increasing apoptosis. Similarly, specific inhibitors of either MMP-2 or -9, or of both gelatinases (Ro28-2653) and a selective knockdown of MMP-2/-9 mRNA expression blocked calcification of murine VSMC induced by calcification medium (CM). In contrast to MMP inhibition, recombinant MMP-2 or MMP-9 enhanced CM-induced calcifications and the secretion of gelatinases. These data indicate that both gelatinases provide essential signals for phenotypic VSMC conversion, matrix remodelling and the initiation of vascular calcification. Their inhibition seems a promising strategy in the prevention of vascular calcifications.}, language = {en} } @article{LiChenDongetal.2014, author = {Li, Jian and Chen, You-Peng and Dong, Yun-Peng and Yu, Cal-Hong and Lu, Yong-Ping and Xiao, Xiao-Min and Hocher, Berthold}, title = {The impact of umbilical blood flow regulation on fetal development differs in diabetic and non-diabetic pregnancy}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, volume = {39}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, number = {4}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000355815}, pages = {369 -- 377}, year = {2014}, abstract = {Background/Aims: Diabetes is well-known to influence endothelial function. Endothelial function and blood flow regulation might be different in diabetic and non-diabetic pregnancy. However, the impact of umbilical blood flow regulation in gestational diabetes on fetal development is unknown so far. Methods: In a prospective birth cohort study, we analyzed the association of the umbilical artery Doppler indices (pulsatility index, resistance index and systolic/diastolic ratio) and fetal size measures (biparietal diameter, head circumference, abdominal circumference, femur length and birth weight) in 519 non-gestational diabetes mellitus pregnancies (controls) and 226 gestational diabetes mellitus pregnancies in middle (day 160.32 +/- 16.29 of gestation) and late (day 268.12 +/- 13.04 of gestation) pregnancy. Results: Multiple regression analysis considering confounding factors (gestational day of ultrasound examination, offspring sex, maternal body mess index before pregnancy, maternal age at delivery, maternal body weight at delivery and maternal hypertension) showed that umbilical artery Doppler indices (pulsatility index, resistance index and systolic/diastolic ratio) were associated with fetal head circumference and femur length in middle gestational diabetes mellitus pregnancy but not in non-gestational diabetes mellitus pregnancy. Head circumference, biparietal diameter, abdominal circumference and femur length in mid gestation were smaller in fetus of gestational diabetes mellitus pregnancy versus non-gestational diabetes mellitus pregnancy. In contrast to non-gestational diabetes mellitus pregnancy in late gestation, umbilical artery Doppler indices in gestational diabetes mellitus pregnancy were not associated with ultrasound measures of fetal growth. Birth weight was slightly increased in gestational diabetes mellitus pregnancy as compared to non-gestational diabetes mellitus pregnancy. Conclusions: The impact of umbilical blood flow on fetal growth is time dependent in human gestational diabetes mellitus and non-gestational diabetes mellitus pregnancy. In gestational diabetes mellitus pregnancy umbilical blood flow is critical for organ development in much earlier stages of pregnancy as compared to non-gestational diabetes mellitus pregnancy. The physiological and molecular pathways why there is a catch up growth in later times of gestational diabetes mellitus pregnancy resulting in larger gestational diabetes mellitus babies at birth needs to be addressed in further studies.}, language = {en} } @article{MiddeldorpMahajanHorikoshietal.2019, author = {Middeldorp, Christel M. and Mahajan, Anubha and Horikoshi, Momoko and Robertson, Neil R. and Beaumont, Robin N. and Bradfield, Jonathan P. and Bustamante, Mariona and Cousminer, Diana L. and Day, Felix R. and De Silva, N. Maneka and Guxens, Monica and Mook-Kanamori, Dennis O. and St Pourcain, Beate and Warrington, Nicole M. and Adair, Linda S. and Ahlqvist, Emma and Ahluwalia, Tarunveer Singh and Almgren, Peter and Ang, Wei and Atalay, Mustafa and Auvinen, Juha and Bartels, Meike and Beckmann, Jacques S. and Bilbao, Jose Ramon and Bond, Tom and Borja, Judith B. and Cavadino, Alana and Charoen, Pimphen and Chen, Zhanghua and Coin, Lachlan and Cooper, Cyrus and Curtin, John A. and Custovic, Adnan and Das, Shikta and Davies, Gareth E. and Dedoussis, George V. and Duijts, Liesbeth and Eastwood, Peter R. and Eliasen, Anders U. and Elliott, Paul and Eriksson, Johan G. and Estivill, Xavier and Fadista, Joao and Fedko, Iryna O. and Frayling, Timothy M. and Gaillard, Romy and Gauderman, W. James and Geller, Frank and Gilliland, Frank and Gilsanz, Vincente and Granell, Raquel and Grarup, Niels and Groop, Leif and Hadley, Dexter and Hakonarson, Hakon and Hansen, Torben and Hartman, Catharina A. and Hattersley, Andrew T. and Hayes, M. Geoffrey and Hebebrand, Johannes and Heinrich, Joachim and Helgeland, Oyvind and Henders, Anjali K. and Henderson, John and Henriksen, Tine B. and Hirschhorn, Joel N. and Hivert, Marie-France and Hocher, Berthold and Holloway, John W. and Holt, Patrick and Hottenga, Jouke-Jan and Hypponen, Elina and Iniguez, Carmen and Johansson, Stefan and Jugessur, Astanand and Kahonen, Mika and Kalkwarf, Heidi J. and Kaprio, Jaakko and Karhunen, Ville and Kemp, John P. and Kerkhof, Marjan and Koppelman, Gerard H. and Korner, Antje and Kotecha, Sailesh and Kreiner-Moller, Eskil and Kulohoma, Benard and Kumar, Ashish and Kutalik, Zoltan and Lahti, Jari and Lappe, Joan M. and Larsson, Henrik and Lehtimaki, Terho and Lewin, Alexandra M. and Li, Jin and Lichtenstein, Paul and Lindgren, Cecilia M. and Lindi, Virpi and Linneberg, Allan and Liu, Xueping and Liu, Jun and Lowe, William L. and Lundstrom, Sebastian and Lyytikainen, Leo-Pekka and Ma, Ronald C. W. and Mace, Aurelien and Magi, Reedik and Magnus, Per and Mamun, Abdullah A. and Mannikko, Minna and Martin, Nicholas G. and Mbarek, Hamdi and McCarthy, Nina S. and Medland, Sarah E. and Melbye, Mads and Melen, Erik and Mohlke, Karen L. and Monnereau, Claire and Morgen, Camilla S. and Morris, Andrew P. and Murray, Jeffrey C. and Myhre, Ronny and Najman, Jackob M. and Nivard, Michel G. and Nohr, Ellen A. and Nolte, Ilja M. and Ntalla, Ioanna and Oberfield, Sharon E. and Oken, Emily and Oldehinkel, Albertine J. and Pahkala, Katja and Palviainen, Teemu and Panoutsopoulou, Kalliope and Pedersen, Oluf and Pennell, Craig E. and Pershagen, Goran and Pitkanen, Niina and Plomin, Robert and Power, Christine and Prasad, Rashmi B. and Prokopenko, Inga and Pulkkinen, Lea and Raikkonen, Katri and Raitakari, Olli T. and Reynolds, Rebecca M. and Richmond, Rebecca C. and Rivadeneira, Fernando and Rodriguez, Alina and Rose, Richard J. and Salem, Rany and Santa-Marina, Loreto and Saw, Seang-Mei and Schnurr, Theresia M. and Scott, James G. and Selzam, Saskia and Shepherd, John A. and Simpson, Angela and Skotte, Line and Sleiman, Patrick M. A. and Snieder, Harold and Sorensen, Thorkild I. A. and Standl, Marie and Steegers, Eric A. P. and Strachan, David P. and Straker, Leon and Strandberg, Timo and Taylor, Michelle and Teo, Yik-Ying and Thiering, Elisabeth and Torrent, Maties and Tyrrell, Jessica and Uitterlinden, Andre G. and van Beijsterveldt, Toos and van der Most, Peter J. and van Duijn, Cornelia M. and Viikari, Jorma and Vilor-Tejedor, Natalia and Vogelezang, Suzanne and Vonk, Judith M. and Vrijkotte, Tanja G. M. and Vuoksimaa, Eero and Wang, Carol A. and Watkins, William J. and Wichmann, H-Erich and Willemsen, Gonneke and Williams, Gail M. and Wilson, James F. and Wray, Naomi R. and Xu, Shujing and Xu, Cheng-Jian and Yaghootkar, Hanieh and Yi, Lu and Zafarmand, Mohammad Hadi and Zeggini, Eleftheria and Zemel, Babette S. and Hinney, Anke and Lakka, Timo A. and Whitehouse, Andrew J. O. and Sunyer, Jordi and Widen, Elisabeth E. and Feenstra, Bjarke and Sebert, Sylvain and Jacobsson, Bo and Njolstad, Pal R. and Stoltenberg, Camilla and Smith, George Davey and Lawlor, Debbie A. and Paternoster, Lavinia and Timpson, Nicholas J. and Ong, Ken K. and Bisgaard, Hans and Bonnelykke, Klaus and Jaddoe, Vincent W. V. and Tiemeier, Henning and Jarvelin, Marjo-Riitta and Evans, David M. and Perry, John R. B. and Grant, Struan F. A. and Boomsma, Dorret I. and Freathy, Rachel M. and McCarthy, Mark I. and Felix, Janine F.}, title = {The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia}, series = {European journal of epidemiology}, volume = {34}, journal = {European journal of epidemiology}, number = {3}, publisher = {Springer}, address = {Dordrecht}, organization = {EArly Genetics Lifecourse EGG Consortium EGG Membership EAGLE Membership}, issn = {0393-2990}, doi = {10.1007/s10654-019-00502-9}, pages = {279 -- 300}, year = {2019}, abstract = {The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.}, language = {en} } @article{TsuprykovAndoReichetzederetal.2016, author = {Tsuprykov, Oleg and Ando, Ryotaro and Reichetzeder, Christoph and von Websky, Karoline and Antonenko, Viktoriia and Sharkovska, Yuliya and Chaykovska, Lyubov and Rahnenfuehrer, Jan and Hasan, Ahmed Abdallah Abdalrahman Mohamed and Tammen, Harald and Alter, Markus L. and Klein, Thomas and Ueda, Seiji and Yamagishi, Sho-ichi and Okuda, Seiya and Hocher, Berthold}, title = {The dipeptidyl peptidase inhibitor linagliptin and the angiotensin II receptor blocker telmisartan show renal benefit by different pathways in rats with 5/6 nephrectomy}, series = {Kidney international : official journal of the International Society of Nephrology}, volume = {89}, journal = {Kidney international : official journal of the International Society of Nephrology}, publisher = {Nature Publ. Group}, address = {New York}, issn = {0085-2538}, doi = {10.1016/j.kint.2016.01.016}, pages = {1049 -- 1061}, year = {2016}, abstract = {Dipeptidyl peptidase (DPP)-4 inhibitors delay chronic kidney disease (CKD) progression in experimental diabetic nephropathy in a glucose-independent manner. Here we compared the effects of the DPP-4 inhibitor linagliptin versus telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. Animals were allocated to 1 of 4 groups: sham operated plus placebo; 5/6 nephrectomy plus placebo; 5/6 nephrectomy plus linagliptin; and 5/6 nephrectomy plus telmisartan. Interstitial fibrosis was significantly decreased by 48\% with linagliptin but a non-significant 24\% with telmisartan versus placebo. The urine albumin-to-creatinine ratio was significantly decreased by 66\% with linagliptin and 92\% with telmisartan versus placebo. Blood pressure was significantly lowered by telmisartan, but it was not affected by linagliptin. As shown by mass spectrometry, the number of altered peptide signals for linagliptin in plasma was 552 and 320 in the kidney. For telmisartan, there were 108 peptide changes in plasma and 363 in the kidney versus placebo. Linagliptin up-regulated peptides derived from collagen type I, apolipoprotein C1, and heterogeneous nuclear ribonucleoproteins A2/B1, a potential downstream target of atrial natriuretic peptide, whereas telmisartan up-regulated angiotensin II. A second study was conducted to confirm these findings in 5/6 nephrectomy wild-type and genetically deficient DPP-4 rats treated with linagliptin or placebo. Linagliptin therapy in wild-type rats was as effective as DPP-4 genetic deficiency in terms of albuminuria reduction. Thus, linagliptin showed comparable efficacy to telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. However, the underlying pathways seem to be different. Copyright (C) 2016, International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).}, language = {en} } @article{LuLungXiaoetal.2014, author = {Lu, Yong-Ping and Lung, Xu-Jing and Xiao, Xiao-Min and Huang, Si-Min and Liu, Zhi-Wei and Li, Jian and Hocher, Berthold and Chen, You-Peng}, title = {Telbivudine during the second and third trimester of pregnancy interrupts HBV intrauterine transmission: a systematic review and meta-analysis}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {60}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {4}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2013.130408}, pages = {571 -- 586}, year = {2014}, abstract = {Beckground: Evaluate the efficacy and safety of telbivudine during the 2nd and 3rd trimester of pregnancy in intrauterine transmission of hepatitis B virus (HBV). Based on the principle of Cochrane systematic reviews, a database was constructed from Medline, EMBASE, Cochrane Library, the US National Science Digital Library (NSDL), the China Biological Medicine Database (CBM-disc), and contact with Chinese experts in the field from November 2006 to February 2013. Results: Either the Mantel-Haenszel or Inverse Variance fixed-effects model or Mantel-Haenszel or Inverse Variance random-effects model was applied for all analyses indicated by odds ratio (OR) and 95\% confidence interval (CI). The meta-analysis based on new onset of HBsAg seropositivity of infants at 6 - 12 months postpartum revealed that the control group had an intrauterine transmission rate of 8.25 - 42.31\%. This rate was reduced to 0 - 14.29\% in the telbivudine treatment group (OR 0.09, 95\% CI 0.04 - 0.22, including seven trials, p < 0.001). The rates of intrauterine transmission based on new onset of HBV DNA seropositivity of infants at 6 - 12 months postpartum were 8.25 - 19.23\% in the control group and 0 - 3.57\% in the treatment group (OR 0.07, 95\% CI 0.02 - 0.22, p < 0.001, including only five trials, since two trials had no data on HBV DNA in infants). With the exception of CK elevations, adverse effect frequencies were similar in both groups. Conclusions: Telbivudine is an effective and safe drug for preventing intrauterine transmission of HBV.}, language = {en} } @article{SatwikoIkedaNakayamaetal.2015, author = {Satwiko, Muhammad Gahan and Ikeda, Koji and Nakayama, Kazuhiko and Yagi, Keiko and Hocher, Berthold and Hirata, Ken-Ichi and Emoto, Noriaki}, title = {Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension}, series = {Biochemical and biophysical research communications}, volume = {465}, journal = {Biochemical and biophysical research communications}, number = {3}, publisher = {Elsevier}, address = {San Diego}, issn = {0006-291X}, doi = {10.1016/j.bbrc.2015.08.002}, pages = {356 -- 362}, year = {2015}, abstract = {Pulmonary arterial hypertension (PAH) is a fatal disease that eventually results in right heart failure and death. Current pharmacologic therapies for PAH are limited, and there are no drugs that could completely cure PAH. Enhanced activity of endothelin system has been implicated in PAH severity and endothelin receptor antagonists have been used clinically to treat PAH. However, there is limited experimental evidence on the direct role of enhanced endothelin system activity in PAL-I. Here, we investigated the correlation between endothelin-1 (ET-1) and PAH using ET-1 transgenic (ETTG) mice. Exposure to chronic hypoxia increased right ventricular pressure and pulmonary arterial wall thickness in ETTG mice compared to those in wild type mice. Of note, ETTG mice exhibited modest but significant increase in right ventricular pressure and vessel wall thickness relative to wild type mice even under normoxic conditions. To induce severe PAH, we administered SU5416, a vascular endothelial growth factor receptor inhibitor, combined with exposure to chronic hypoxia. Treatment with SU5416 modestly aggravated hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial vessel wall thickening in ETTG mice in association with increased interleukin-6 expression in blood vessels. However, there was no sign of obliterative endothelial cell proliferation and plexiform lesion formation in the lungs. These results demonstrated that enhanced endothelin system activity could be a causative factor in the development of PAH and provided rationale for the inhibition of endothelin system to treat PAH. (C) 2015 Elsevier Inc. All rights reserved.}, language = {en} } @article{GeschkaKretschmerSharkovskaetal.2011, author = {Geschka, Sandra and Kretschmer, Axel and Sharkovska, Yuliya and Evgenov, Oleg V. and Lawrenz, Bettina and Hucke, Andreas and Hocher, Berthold and Stasch, Johannes-Peter}, title = {Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in salt-sensitive dahl rats}, series = {PLoS one}, volume = {6}, journal = {PLoS one}, number = {7}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0021853}, pages = {10}, year = {2011}, abstract = {Background: A direct pharmacological stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of various cardiovascular disorders associated with endothelial dysfunction. Novel sGC stimulators, including riociguat (BAY 63-2521), have a dual mode of action: They sensitize sGC to endogenously produced nitric oxide (NO) and also directly stimulate sGC independently of NO. Little is known about their effects on tissue remodeling and degeneration and survival in experimental malignant hypertension. Methods and Results: Mortality, hemodynamics and biomarkers of tissue remodeling and degeneration were assessed in Dahl salt-sensitive rats maintained on a high salt diet and treated with riociguat (3 or 10 mg/kg/d) for 14 weeks. Riociguat markedly attenuated systemic hypertension, improved systolic heart function and increased survival from 33\% to 85\%. Histological examination of the heart and kidneys revealed that riociguat significantly ameliorated fibrotic tissue remodeling and degeneration. Correspondingly, mRNA expression of the pro-fibrotic biomarkers osteopontin (OPN), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in the myocardium and the renal cortex was attenuated by riociguat. In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1. Conclusions: Stimulation of sGC by riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload. These findings suggest a therapeutic potential of sGC stimulators in diseases associated with impaired cardiovascular and renal functions.}, language = {en} } @article{ScholzeLiuPedersenetal.2014, author = {Scholze, Alexandra and Liu, Ying and Pedersen, Lise and Xia, Shengqiang and Roth, Heinz J. and Hocher, Berthold and Rasmussen, Lars Melholt and Tepel, Martin}, title = {Soluble alpha-Klotho and its relation to kidney function and fibroblast growth factor-23}, series = {The journal of clinical endocrinology \& metabolism}, volume = {99}, journal = {The journal of clinical endocrinology \& metabolism}, number = {5}, publisher = {Endocrine Society}, address = {Washington}, issn = {0021-972X}, doi = {10.1210/jc.2013-4171}, pages = {E855 -- E861}, year = {2014}, abstract = {Context: Relations between fibroblast growth factor-23 (FGF-23), soluble alpha-klotho (s-alpha-klotho), and kidney function in chronic kidney disease (CKD) are still unclear. Especially the role of s-alpha-klotho requires further study. Objectives: Our objectives were to analyze the relation of s-alpha-klotho to estimated glomerular filtration rate (eGFR), FGF-23, and other parameters of calcium-phosphate metabolism and to investigate the response of s-alpha-klotho to cholecalciferol. Patients, Design, and Setting: Twenty-four CKD (stage 1-5) patients participated in this 8-week randomized controlled trial (vitamin D and chronic renal insufficiency). Interventions: Interventions included 40 000 IU cholecalciferol or placebo weekly. Main Outcome Measure: S-alpha-klotho was determined by ELISA with antihuman klotho antibodies 67G3 and 91F1. Results: For all patients, s-alpha-klotho concentrations did not differ between CKD stages. When patients were subdivided based on FGF-23 concentrations, a positive association of s-alpha-klotho with eGFR became apparent in patients with lower than median FGF-23 concentrations but not in those above median value. Patients with s-alpha-klotho below 204 pg/mL showed higher age, lower phosphate clearance, and lower bone-specific alkaline phosphatase compared with patients with higher s-alpha-klotho. Treatment with cholecalciferol significantly increased 1,25-dihydroxyvitamin D. The increase of FGF-23 had only borderline significance. There was no significant effect of high-dose cholecalciferol administration for 8 weeks on plasma s-alpha-klotho. Conclusions: CKD patients with s-alpha-klotho below 204 pg/mL had higher age, lower phosphate clearance, and lower bone-specific alkaline phosphatase. An association of s-alpha-klotho with eGFR was observed only in the presence of close to normal, but not high, FGF-23 concentrations. Cholecalciferol treatment did not change s-alpha-klotho concentrations.}, language = {en} } @article{SharkovskaKalkvonWebskyetal.2011, author = {Sharkovska, Yuliya and Kalk, Philipp and von Websky, Karoline and Relle, Katharina and Pfab, Thiemo and Alter, Markus L. and Fischer, Yvan and Hocher, Berthold}, title = {Renoprotective effects of combined endothelin-converting enzyme/neutral endopeptidase inhibitor SLV338 in acute and chronic experimental renal damage}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {57}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {7-8}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, pages = {507 -- 515}, year = {2011}, abstract = {Background: Acute kidney injury (AKI) as well as chronic renal failure are associated with a huge mortality/morbidity. However, so far no drugs have been approved for the treatment of acute kidney failure and only a few for the treatment of chronic kidney disease (CKD). We analysed the effect of SLV 338, a neutral endopeptidase (NEP)/endothelin converting enzyme (ECE)-inhibitor in animal models of acute kidney failure as well as chronic renal failure. Methods: Acute renal failure was induced in male Wistar rats by uninephrectomy and clamping of the remaining kidney for 55 minutes. SLV338 (total dose: 4.9 mg/kg) or vehicle was continuously infused for 2 hours (starting 20 minutes prior to clamping). Sham operated animals served as controls. Plasma creatinine was measured at baseline and day 2 and 8 after renal ischemia-reperfusion. Hypertensive renal damage was induced in male Sprague Dawley rats by nitric oxide deficiency using L-NAME (50 mg/kg per day, added to drinking water for 4 weeks). One group was treated over the same time period with SLV338 (30 mg/kg per day, mixed with food). Systolic blood pressure was monitored weekly. At study end, urine and blood samples were collected and kidneys were harvested. Results: Acute renal ischemia-reperfusion caused a 5-fold plasma creatinine elevation (day 2), which was significantly attenuated by more than 50 \% in animals treated with SLV338 (p < 0.05). Renal failure was accompanied by a 67 \% mortality in vehicle-treated rats, but only 20 \% after SLV338 treatment (p = 0.03 compared to sham controls). Chronic L-NAME administration caused hypertension, urinary albumin excretion, glomerulosclerosis, renal arterial remodelling, and renal interstitial fibrosis. Treatment with SLV338 did not significantly affect blood pressure, but abolished renal tissue damage (interstitial fibrosis, glomerulosclerosis, renal arterial remodelling (p < 0.05 versus L-NAME group in each case). Conclusions: The dual ECE/NEP inhibitor SLV338 preserves kidney function and reduces mortality in severe acute ischemic renal failure. Moreover, combined ECE/NEP inhibition prevents hypertensive renal tissue damage in a blood pressure independent manner in L-NAME-treated rats.}, language = {en} } @article{ChenLiWangetal.2012, author = {Chen, You-Peng and Li, Jian and Wang, Zi-Neng and Reichetzeder, Christoph and Xu, Hao and Gong, Jian and Chen, Guang-Ji and Pfab, Thiemo and Xiao, Xiao-Min and Hocher, Berthold}, title = {Renin angiotensin aldosterone system and glycemia in pregnancy}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {5-6}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, pages = {527 -- 533}, year = {2012}, abstract = {Background: The renin-angiotensin-aldosterone system (RAAS) is involved in the pathogenesis of insulin resistance and type 2 diabetes in the general population. The RAAS is activated during pregnancy. However, it is unknown whether the RAAS contributes to glycemia in pregnant women. Methods: Plasma renin activity (PRA) and plasma aldosterone levels were quantified at delivery in 689 Chinese mothers. An oral glucose tolerance test in fasted women was performed in the second trimester of pregnancy. The diagnosis of gestational diabetes mellitus (GDM) and impaired glucose tolerance during pregnancy were made according to the guidelines of the Chinese Society of Obstetrics. Results: Plasma aldosterone was significantly higher in pregnant women with GDM as compared to those without impairment of glycemic control (normal pregnancies: 0.27 +/- 0.21 ng/mL, GDM: 0.36 +/- 0.30 ng/mL; p<0.05). Regression analyses revealed that PRA was negatively correlated with fasting blood glucose (FBG) (R-2 = 0.03, p = 0.007), whereas plasma aldosterone and aldosterone/PRA ratio were positively correlated with FBG (R-2 = 0.05, p<0.001 and R-2 = 0.03, p = 0.007, respectively). Multivariable regression analysis models considering relevant confounding factors confirmed these findings. Conclusions: This study demonstrated that fasting blood glucose in pregnant women is inversely correlated with the PRA, whereas plasma aldosterone showed a highly significant positive correlation with fasting blood glucose during pregnancy. Moreover, plasma aldosterone is significantly higher in pregnant women with GDM as compared to those women with normal glucose tolerance during pregnancy. Although causality cannot be proven in association studies, these data may indicate that the RAAS during pregnancy contributes to the pathogenesis of insulin resistance/new onset of diabetes during pregnancy.}, language = {en} } @article{SchmerbachKalkWengenmayeretal.2012, author = {Schmerbach, K. and Kalk, Philipp. and Wengenmayer, Christina and Lucht, K. and Unger, T. and Hocher, Berthold and Thoene-Reineke, C.}, title = {Renal outcome in equipotent Antihypertensive Treatment with Telmisartan, Ramipril and in combination in SHR-SP Rats}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {7-8}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2011.110622}, pages = {625 -- 633}, year = {2012}, abstract = {Background: The ONTARGET trial revealed an association of ACEI/ARB combination treatment (telmisartan and ramipril) with adverse renal outcome versus respective monotherapy; preclinical evidence regarding renal outcome in ACEI/ARB combination treatment is scarce. Methods: Spontaneously hypertensive stroke prone rats (SHR-SP) rats on a salt-rich diet were randomly allocated to 4 groups: SHR (untreated, n = 24), SHR + telmisartan (SHR-T, 2.39 +/- 0.69 mg/kg bw; n = 27), SHR + ramipril (SHR-R, 6.28 +/- 3.48 mg/kg bw; n = 27) and combination treatment (SHR-TR, 0.51 +/- 0.14 mg/kg bw; same dose for telmisartan and ramipril; n = 26). Study duration was 12 weeks, blood pressure was assessed weekly and doses were adjusted to maintain equal blood pressure. Finally, blood and urine samples were obtained and kidneys were harvested for histological studies. Results: Blood pressure in untreated rats rose to a maximum of 239 mmHg, whereas in all treatment groups it remained stable betvveen 140 and 150 mmHg. Mortality was 50\% in the untreated group, whereas all treatment groups survived completely. Renal function - as indicated by plasma urea and cystatin c - was significantly worse in SHR-TR animals compared to all other groups. With plasma creatinine a similar trend was observed. All treatment options significantly decreased albuminuria. Renal glomerulosclerosis was decreased by monotherapy, whereas combination therapy failed to have a significant effect. Interstitial fibrosis was decreased to a similar extent by all treatment options. Conclusions: ACEI/ARB combination treatment failed to render significant additional benefits on renal outcome in hypertensive rats when compared to monotherapy. Instead our data indicate that dual RAAS blockade might have an adverse effect on kidney function and histology when compared to monotherapy in salt-loaded SHR-SP.}, language = {en} } @article{HocherHeidenvonWebskyetal.2011, author = {Hocher, Berthold and Heiden, Susi and von Websky, Karoline and Arafat, Ayman M. and Rahnenf{\"u}hrer, Jan and Alter, Markus L. and Kalk, Philipp and Ziegler, Dieter and Fischer, Yvan and Pfab, Thiemo}, title = {Renal effects of the novel selective adenosine A(1) receptor blocker SLV329 in experimental liver cirrhosis in rats}, series = {PLoS one}, volume = {6}, journal = {PLoS one}, number = {3}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0017891}, pages = {8}, year = {2011}, abstract = {Liver cirrhosis is often complicated by an impaired renal excretion of water and sodium. Diuretics tend to further deteriorate renal function. It is unknown whether chronic selective adenosine A(1) receptor blockade, via inhibition of the hepatorenal reflex and the tubuloglomerular feedback, might exert diuretic and natriuretic effects without a reduction of the glomerular filtration rate. In healthy animals intravenous treatment with the novel A(1) receptor antagonist SLV329 resulted in a strong dose-dependent diuretic (up to 3.4-fold) and natriuretic (up to 13.5-fold) effect without affecting creatinine clearance. Male Wistar rats with thioacetamide-induced liver cirrhosis received SLV329, vehicle or furosemide for 12 weeks. The creatinine clearance of cirrhotic animals decreased significantly (-36.5\%, p < 0.05), especially in those receiving furosemide (-41.9\%, p < 0.01). SLV329 was able to prevent this decline of creatinine clearance. Mortality was significantly lower in cirrhotic animals treated with SLV329 in comparison to animals treated with furosemide (17\% vs. 54\%, p < 0.05). SLV329 did not relevantly influence the degree of liver fibrosis, kidney histology or expression of hepatic or renal adenosine receptors. In conclusion, chronic treatment with SLV329 prevented the decrease of creatinine clearance in a rat model of liver cirrhosis. Further studies will have to establish whether adenosine A(1) receptor antagonists are clinically beneficial at different stages of liver cirrhosis.}, language = {en} } @article{StaschSchlossmannHocher2015, author = {Stasch, Johannes-Peter and Schlossmann, Jens and Hocher, Berthold}, title = {Renal effects of soluble guanylate cyclase stimulators and activators: A review of the preclinical evidence}, series = {Current opinion in pharmacology}, volume = {21}, journal = {Current opinion in pharmacology}, publisher = {Elsevier}, address = {Oxford}, issn = {1471-4892}, doi = {10.1016/j.coph.2014.12.014}, pages = {95 -- 104}, year = {2015}, abstract = {Direct stimulation of soluble guanylate cyclase (sGC) is emerging as a potential new approach for the treatment of renal disorders. sGC catalyzes the formation of cyclic guanosine monophosphate (cGMP), deficiency of which is implicated in the pathogenesis of chronic kidney disease (CKD). Therefore, new classes of drugs sGC stimulators and activators are being investigated in preclinical models under conditions where nitric oxide is deficient. In preclinical models with different etiologies of CKD, the sGC stimulators BAY 41-2272, BAY 41-8543, BAY 60-4552, riociguat and vericiguat and the sGC activators cinaciguat, ataciguat, BI 703704 and GSK2181236A have shown consistently renoprotective effects. Clinical trials are required to confirm these findings in humans, and to ascertain whether these agents could provide a future alternative to guideline-recommended treatments.}, language = {en} } @article{DschietzigKrauseRelleHennequinetal.2015, author = {Dschietzig, Thomas Bernd and Krause-Relle, Katharina and Hennequin, Maud and von Websky, Karoline and Rahnenfuhrer, Jan and Ruppert, Jana and Groena, Hans Juergen and Armbruster, Franz Paul and Bathgate, Ross A. D. and Aschenbach, Joerg R. and Forssmann, Wolf-Georg and Hocher, Berthold}, title = {Relaxin-2 does not Ameliorate Nephropathy in an experimental model of Type-1 Diabetes}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, volume = {40}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, number = {1}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000368484}, pages = {77 -- 88}, year = {2015}, abstract = {Background/Aims: In diabetic nephropathy (DN), the current angiotensin-II-blocking pharmacotherapy is frequently failing. For diabetic cardiomyopathy (DC), there is no specific remedy available. Relaxin-2 (Rlx) - an anti-fibrotic, anti-inflammatory, and vasoprotecting peptide - is a candidate drug for both. Methods: Low-dose (32 mu g/kg/day) and high-dose (320 mu g/kg/day) Rlx were tested against vehicle (n = 20 each) and non-diabetic controls (n = 14) for 12 weeks in a model of type-1 diabetes induced in endothelial nitric oxide synthase knock-out (eNOS-KO) mice by intraperitoneal injection of streptozotocin. Results: Diabetic animals showed normal plasma creatinine, markedly increased albuminuria and urinary malonyldialdehyde, elevated relative kidney weight, glomerulosclerosis, and increased glomerular size, but no relevant interstitial fibrosis. Neither dose of Rlx affected these changes although the drug was active and targeted plasma levels were achieved. Of note, we found no activation of the renal TGF-beta pathway in this model. In the hearts of diabetic animals, no fibrotic alterations indicative of DC could be determined which precluded testing of the initial hypothesis. Conclusions: We investigated a model showing early DN without overt tubulo-interstitial fibrosis and activation of the TGF-beta-Smad-2/3 pathway. In this model, Rlx proved ineffective; however, the same may not apply to other models and types of diabetes.}, language = {en} } @article{TsuprykovBuseSkobloetal.2018, author = {Tsuprykov, Oleg and Buse, Claudia and Skoblo, Roman and Haq, Afrozul and Hocher, Berthold}, title = {Reference intervals for measured and calculated free 25-hydroxyvitamin D in normal pregnancy}, series = {The Journal of Steroid Biochemistry and Molecular Biology}, volume = {181}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, publisher = {Elsevier}, address = {Oxford}, issn = {0960-0760}, doi = {10.1016/j.jsbmb.2018.03.005}, pages = {80 -- 87}, year = {2018}, abstract = {The determination of free 25-hydroxyvitamin D (25(OH)D) as compared to the analysis of total 25-hydroxyvitamin D might reflect better the vitamin D status during pregnancy, since vitamin D-binding protein (DBP) concentrations increase throughout pregnancy and the vast majority of 25(OH)D is tightly bound to DBP thus strongly influencing total 25(OH)D. The concentration of the biologically active free 25(OH)D - on the other hand - is much less dependent on the DBP concentrations. The study was conducted in May-June 2016 in 368 Caucasian pregnant healthy women - residents of Northeastern Germany. Free 25(OH)D was either measured directly by commercial ELISA kit or assessed by calculation via total 25(OH)D, DBP, and albumin serum concentrations. Regardless of the detection method, free 25(OH)D lowers in the 3rd trimester comparing to the 1st trimester (by 12\% and 21\%, p < 0.05 and p < 0.001, for measured and calculated free 25(OH)D, respectively), whereas total 25(OH)D was not decreased in late pregnancy. DBP rises with gestational age. Total 25(OH)D was not correlated with serum calcium (p = 0.251), whereas free 25(OH)D was significantly (p = 0.007 for measured free 25(OH)D and p < 0.001 for calculated free 25(OH)D) positively correlated with calcium. All 25(OH) D isoforms were significantly negatively correlated with bone-specific alkaline phosphatase (BSAP), however the correlation strength was the lowest with total 25(OH)D (rho = -0.108, p = 0.038), whereas both measured and calculated free 25(OH)D revealed better associations with BSAP (rho = -0.203 and rho = -0.211 for measured and calculated free 25(OH)D, respectively, p < 0.001 for both). We established pregnancy trimester specific reference intervals for free measured and calculated 25(OH)D and DBP. Both measured and calculated free 25(OH)D showed better correlations with parameters of the endocrine vitamin D system (calcium and BSAP). Both ways of measuring free 25(OH)D in pregnant women are suitable as novel laboratory parameter for vitamin D status monitoring during human pregnancy and might replace in the future the routine total 25(OH)D assessment.}, language = {en} } @article{ReichetzederHeunischvonEinemetal.2017, author = {Reichetzeder, Christoph and Heunisch, Fabian and von Einem, Gina-Franziska and Tsuprykov, Oleg and Kellner, Karl-Heinz and Dschietzig, Thomas and Kretschmer, Axel and Hocher, Berthold}, title = {Pre-interventional kynurenine predicts medium-term outcome after contrast media exposure due to coronary angiography}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft}, volume = {42}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft}, number = {2}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000477222}, pages = {244 -- 256}, year = {2017}, abstract = {Background/Aims: Contrast induced acute kidney injury (CI-AKI) remains a serious complication of contrast media enhanced procedures like coronary angiography. There is still a lack of established biomarkers that help to identify patients at high risk for short and long-term complications. The aim of the current study was to evaluate plasma kynurenine as a predictive biomarker for CI-AKI and long-term complications, measured by the combined endpoint "major adverse kidney events" (MAKE) up to 120 days after CM application. Methods: In this prospective cohort study 245 patients undergoing coronary angiography were analyzed. Blood samples were obtained at baseline, 24h and 48h after contrast media (CM) application to diagnose CI-AKI. Patients were followed for 120 days for adverse clinical events including death, the need for dialysis, and a doubling of plasma creatinine. Occurrence of any of these events was summarized in the combined endpoint MAKE. Results: Preinterventional plasma kynurenine was not associated with CI-AKI. Patients who later developed MAKE displayed significantly increased preinterventional plasma kynurenine levels (p<0.0001). ROC analysis revealed that preinterventional kynurenine is highly predictive for MAKE (AUC=0.838; p<0.0001). The optimal cutoff was found at >= 3.5 mu mol/L. Using this cutoff, the Kaplan-Meier estimator demonstrated that concentrations of plasma kynurenine >= 3.5 mu mol/L were significantly associated with a higher prevalence of MAKE until follow up (p<0.0001). This association remained significant in multivariate Cox regression models adjusted for relevant factors of long-term renal outcome. Conclusion: Preinterventional plasma kynurenine might serve as a highly predictive biomarker for MAKE up to 120 days after coronary angiography.}, language = {en} } @article{LuHasanZengetal.2017, author = {Lu, Yong-Ping and Hasan, Ahmed A. and Zeng, Shufei and Hocher, Berthold}, title = {Plasma ET-1 concentrations are elevated in pregnant women with hypertension - meta-analysis of clinical studies}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft}, volume = {42}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft}, number = {4}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000482004}, pages = {654 -- 663}, year = {2017}, abstract = {Background/Aims: The ET system might be involved in the pathogenesis of hypertensive disorders during pregnancy. The objective is to analyse the impact of ET-1 in hypertensive pregnant women by a strict meta-analysis of published human clinical studies. Methods: Based on the principle of Cochrane systematic reviews, Cohort studies in PubMed (Medline), Google Scholar and China Biological Medicine Database (CBM-disc) designed to identify the role of endothelin-1 (ET-1) in the pathophysiology of gestational hypertension and preeclampsia were screened. Review Manager Version 5.0 (Rev-Man 5.0) was applied for statistical analysis. Mean difference and 95\% confidence interval (CI) were shown in inverse variance (IV) fixed-effects model or IV random-effects model. Results: Sixteen published cohort studies including 1739 hypertensive cases and 409 controls were used in the meta-analysis. ET-1 plasma concentrations were higher in hypertensive pregnant women as compared to the controls (mean difference between groups: 19.02 [15.60～22.44], P < 0.00001,). These finding were driven by severity of hypertension and/or degree of proteinuria. Conclusion: Plasma ET-1 concentrations are elevated in hypertensive disorders during human pregnancy. In particular women with preeclampsia (hypertensive pregnant women with proteinuria) have substantially elevated plasma ET-1 concentration as compared to pregnant women with normal blood pressure.}, language = {en} } @article{XuLuHasanetal.2017, author = {Xu, Mei and Lu, Yong-Ping and Hasan, Ahmed A. and Hocher, Berthold}, title = {Plasma ET-1 concentrations are elevated in patients with hypertension meta-analysis of clinical studies}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft}, volume = {42}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft}, number = {2}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000477572}, pages = {304 -- 313}, year = {2017}, abstract = {Background/Aims: A recent study revealed that global overexpression of ET-1 causes a slight reduction in systemic blood pressure. Moreover, heterozygous ET-1 knockout mice are hypertensive. The role of ET-1 in human hypertension was so far not addressed by a strict meta-analysis of published human clinical studies. Methods: We included studies published between January 1, 1990 and February 28, 2017. We included case control studies analyzing untreated essential hypertension or hypertensive patients where antihypertensive medication was discontinued for at least two weeks. Based on the principle of Cochrane systematic reviews, case control studies (CCSs) in PubMed (Medline) and Google Scholar designed to identify the role of endothelin-1 (ET-1) in the pathophysiological of hypertension were screened. Review Manager Version 5.0 (Rev-Man 5.0) was applied for statistical analysis. Mean difference and 95\% confidence interval (CI) were shown in inverse variance (IV) fixed-effects model or IV random-effects models. Results: Eleven studies fulfilling our in-and exclusion criteria were eligible for this meta-analysis. These studies included 450 hypertensive patients and 328 controls. Our meta-analysis revealed that ET-1 plasma concentrations were higher in hypertensive patients as compared to the control patients [mean difference between groups 1.57 pg/mL, 95\%Ci [0.47 similar to 2.68, P = 0.005]. These finding were driven by patients having systolic blood pressure higher than 160 mmHg and diastolic blood pressure higher than 100 mmHg. Conclusions: This meta-analysis showed that hypertensive patients do have elevated plasma ET-1 concentrations. This finding is driven by those patients with high systolic/diastolic blood pressure. Given that the ET-1 gene did not appear in any of the whole genome association studies searching for hypertension associated gene loci, it is very likely that the elevated plasma ET-1 concentrations in hypertensive patients are secondary to hypertension and may reflect endothelial cell damage.}, language = {en} } @article{ForssmannTillmannHocketal.2016, author = {Forssmann, Wolf-Georg and Tillmann, Hanns-Christian and Hock, Dieter and Forssmann, Kristin and Bernasconi, Corrado and Forssmann, Ulf and Richter, Rudolf and Hocher, Berthold and Pfuetzner, Andreas}, title = {Pharmacokinetic and Pharmacodynamic Characteristics of Subcutaneously Applied PTH-1-37}, series = {German politics}, volume = {41}, journal = {German politics}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000443453}, pages = {507 -- 518}, year = {2016}, abstract = {Background/Aims: Parathyroid hormone (PTH) derivatives exert pronounced renal and osteoanabolic properties when given intermittently. The current study was performed to assess the pharmacokinetic and pharmacodynamic properties as well as safety of subcutaneously applied PTH-1-37 after repeated dosing in healthy subjects. Methods: This randomized, double-blind, dose-escalating, placebo and active comparator controlled study was conducted in 33 healthy postmenopausal women. Subjects were allocated to one of five treatment options: 10, 20, or 40 mu g PTH-1-37, 20 mu g PTH-1-34 or placebo, administered as once daily subcutaneous doses for three days. Plasma drug concentrations and serum levels of endogenous PTH-1-84, and calcium as markers of biological activity were monitored during the treatment. Results: PTH was absorbed rapidly from the subcutaneous tissue with a median t(max) of 30 minutes for 20 and 40 mu g of PTH-1-37. t(max) was 45 minutes for 20 mu g PTH-1-34. Elimination half-lives were estimated as 76 +/- 34 min and 70 +/- 13 min for 20 mu g and 40 mu g PTH-1-37 (mean +/- SD), and 78 +/- 34 for 20 mu g PTH-1-34. Both PTH fragments (PTH-1-37 and PTH-1-34) increased serum calcium. For PTH-1-37 the effect on serum calcium was dose-dependent. Suppression of endogenous PTH-1-84 was seen after the application of both PTH-1-37 and PTH-1-34. During the study period, the subjects experienced no unexpected or serious adverse events. Conclusions: PTH-1-37 is rapidly absorbed after s.c. injection, has a short plasma elimination half-life, and does not accumulate during multiple dosing. Biological activity was demonstrated by rising serum calcium and decreasing endogenous PTH-1-84 in blood plasma. The study drugs were well tolerated and safe. Our investigation presents data that PTH-1-37 is an excellent drug candidate for intervening with syndromes of dysregulation of calcium metabolism. (C) 2016 The Author(s) Published by S. Karger AG, Basel}, language = {en} } @article{ChenXiaoLietal.2012, author = {Chen, You-Peng and Xiao, Xiao-Min and Li, Jian and Reichetzeder, Christoph and Wang, Zi-Neng and Hocher, Berthold}, title = {Paternal body mass index (BMI) is associated with offspring intrauterine growth in a gender dependent manner}, series = {PLoS one}, volume = {7}, journal = {PLoS one}, number = {5}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0036329}, pages = {9}, year = {2012}, abstract = {Background: Environmental alternations leading to fetal programming of cardiovascular diseases in later life have been attributed to maternal factors. However, animal studies showed that paternal obesity may program cardio-metabolic diseases in the offspring. In the current study we tested the hypothesis that paternal BMI may be associated with fetal growth. Methods and Results: We analyzed the relationship between paternal body mass index (BMI) and birth weight, ultrasound parameters describing the newborn's body shape as well as parameters describing the newborns endocrine system such as cortisol, aldosterone, renin activity and fetal glycated serum protein in a birth cohort of 899 father/mother/child triplets. Since fetal programming is an offspring sex specific process, male and female offspring were analyzed separately. Multivariable regression analyses considering maternal BMI, paternal and maternal age, hypertension during pregnancy, maternal total glycated serum protein, parity and either gestational age (for birth weight) or time of ultrasound investigation (for ultrasound parameters) as confounding showed that paternal BMI is associated with growth of the male but not female offspring. Paternal BMI correlated with birth parameters of male offspring only: birth weight; biparietal diameter, head circumference; abdominal diameter, abdominal circumference; and pectoral diameter. Cortisol was likewise significantly correlated with paternal BMI in male newborns only. Conclusions: Paternal BMI affects growth of the male but not female offspring. Paternal BMI may thus represent a risk factor for cardiovascular diseases of male offspring in later life. It remains to be demonstrated whether this is linked to an offspring sex specific paternal programming of cortisol secretion.}, language = {en} } @article{HocherSchlemmHaumannetal.2011, author = {Hocher, Berthold and Schlemm, Ludwig and Haumann, Hannah and Li, Jian and Rahnenf{\"u}hrer, Jan and Guthmann, Florian and Bamberg, Christian and Kalk, Philipp and Pfab, Thiemo and Chen, You-Peng}, title = {Offspring sex determines the impact of the maternal ACE I/D polymorphism on maternal glycaemic control during the last weeks of pregnancy}, series = {Journal of the renin angiotensin aldosterone system}, volume = {12}, journal = {Journal of the renin angiotensin aldosterone system}, number = {3}, publisher = {Sage Publ.}, address = {London}, issn = {1470-3203}, doi = {10.1177/1470320310387843}, pages = {254 -- 261}, year = {2011}, abstract = {Hypothesis/Introduction: We recently demonstrated that fetal sex may affect maternal glycaemic control in genetically prone mothers. We tested the hypothesis that fetal sex/fetal Y/X chromosomes might affect maternal glycaemic control during pregnancy depending on the maternal angiotensin converting enzyme (ACE) I/D polymorphism. Material and methods: One thousand, three hundred and thirty-two Caucasian women without pre-existing diabetes and pre-existing hypertension with singleton pregnancies delivering consecutively at the Charite obstetrics department were genotyped. Glycaemic control was analysed by measuring total glycated haemoglobin at birth. Correction for confounding factors and multiple testing was done. Results: Maternal ACE I/D polymorphism showed significant interaction with fetal sex concerning maternal total glycated haemoglobin. Total glycated haemoglobin in DD mothers delivering boys was 6.42 +/- 0.70\% vs. 6.21 +/- 0.66\% in DD mother delivering girls (p < 0.005), whereas the II carrying mothers showed the opposite effect. II mothers delivering a girl had a higher (p = 0.044) total glycated haemoglobin at birth (6.40 +/- 0.80\%) compared to II mothers delivering boys (6.21 +/- 0.81\%). There was no interaction of the ACE I/D polymorphism and fetal sex with respect to new onset proteinuria, new onset edema and pregnancy-induced hypertension. Conclusions: Maternal glycaemic control during the last weeks of pregnancy seems to be influenced by an interaction of the ACE I/D genotyp and fetal sex.}, language = {en} } @article{WengenmayerKrikovMuelleretal.2011, author = {Wengenmayer, Christina and Krikov, Maxim and Mueller, Susanne and Lucht, Kristin and Villringer, Arno and Hocher, Berthold and Unger, Thomas and Thoene-Reineke, Christa}, title = {Novel therapy approach in primary stroke prevention simultaneous inhibition of endothelin converting enzyme and neutral endopeptidase in spontaneously hypertensive, stroke-prone rats improves survival}, series = {Neurological research : a journal of progress in neurosurgery and neurosciences}, volume = {33}, journal = {Neurological research : a journal of progress in neurosurgery and neurosciences}, number = {2}, publisher = {Routledge, Taylor \& Francis Group}, address = {Leeds}, issn = {0161-6412}, doi = {10.1179/016164111X12881719352534}, pages = {201 -- 207}, year = {2011}, abstract = {Objectives: Stroke, frequently a consequence of hypertension, is one of the leading causes of death and neurological disabilities worldwide. In the ischemic brain, levels of endothelin-1, one of the most potent vasoconstrictors, are raised. Anti-inflammatory and neuroprotective effects of endothelin antagonists after stroke have been described in literature. Based on these findings, we investigated the protective effect of the endothelin converting enzyme/neutral endopeptidase blocker, SLV 338, in salt-loaded, stroke-prone, spontaneously hypertensive rats. Methods: Male, 8-week-old spontaneously hypertensive stroke-prone rats were put on a high salt diet and treated with either 30 mg/kg or 100 mg/kg SLV 338 or vehicle for 27 weeks. Blood pressure, neurological outcome, body weight, and mortality were investigated throughout treatment. In weeks 1 and 9, animals were housed in metabolic cages for collection of urinary and blood samples and assessment of salt water and food intake. In weeks 22 and 27, additional blood samples were taken. At the end of the study, all brains were analyzed using magnetic resonance imaging. Results: SLV 338 was well tolerated in all animals. Neurological outcome and infarct size were similar in all groups. Albuminuria was considerably delayed and the incidence of stroke significantly lowered in treated animals. In spontaneously hypertensive stroke-prone rats, treatment with SLV 338 significantly (P=0.01) improved survival in comparison to the vehicle treated group in a blood pressure-independent manner. Discussion: Our data in spontaneously hypertensive stroke-prone rats demonstrate that combined endothelin converting enzyme/neutral endopeptidase inhibition could offer a new therapeutic approach for primary stroke prevention and improvement of mortality. The mechanism seems to be blood pressure-independent.}, language = {en} } @article{TepelArmbrusterGroenetal.2013, author = {Tepel, Martin and Armbruster, Franz Paul and Groen, Hans Juergen and Scholze, Alexandra and Reichetzeder, Christoph and Roth, Heinz J{\"u}rgen and Hocher, Berthold}, title = {Nonoxidized, biologically active parathyroid hormone determines mortality in hemodialysis patients}, series = {The journal of clinical endocrinology \& metabolism}, volume = {98}, journal = {The journal of clinical endocrinology \& metabolism}, number = {12}, publisher = {Endocrine Society}, address = {Chevy Chase}, issn = {0021-972X}, doi = {10.1210/jc.2013-2139}, pages = {4744 -- 4751}, year = {2013}, abstract = {Background: It was shown that nonoxidized PTH (n-oxPTH) is bioactive, whereas the oxidation of PTH results in a loss of biological activity. Methods: In this study we analyzed the association of n-oxPTH on mortality in hemodialysis patients using a recently developed assay system. Results: Hemodialysis patients (224 men, 116 women) had a median age of 66 years. One hundred seventy patients (50\%) died during the follow-up period of 5 years. Median n-oxPTH levels were higher in survivors (7.2 ng/L) compared with deceased patients (5.0 ng/L; P = .002). Survival analysis showed an increased survival in the highest n-oxPTH tertile compared with the lowest n-oxPTH tertile (chi(2), 14.3; P = 0008). Median survival was 1702 days in the highest n-oxPTH tertile, whereas it was only 453 days in the lowest n-oxPTH tertile. Multivariable-adjusted Cox regression showed that higher age increased odds for death, whereas higher n-oxPTH reduced the odds for death. Another model analyzing a subgroup of patients with intact PTH (iPTH) concentrations at baseline above the upper normal range of the iPTH assay (70 ng/L) revealed that mortality in this subgroup was associated with oxidized PTH but not with n-oxPTH levels. Conclusions: The predictive power of n-oxPTH and iPTH on the mortality of hemodialysis patients differs substantially. Measurements of n-oxPTH may reflect the hormone status more precisely. The iPTH-associated mortality is most likely describing oxidative stress-related mortality.}, language = {en} } @article{SharkovskaKalkLawrenzetal.2010, author = {Sharkovska, Yuliya and Kalk, Philipp and Lawrenz, Bettina and Godes, Michael and Hoffmann, Linda Sarah and Wellkisch, Kathrin and Geschka, Sandra and Relle, Katharina and Hocher, Berthold and Stasch, Johannes-Peter}, title = {Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low- renin and high-renin models}, issn = {0263-6352}, doi = {10.1097/Hjh.0b013e32833b558c}, year = {2010}, abstract = {Objectives The nitric oxide-soluble guanylate cyclase (sGC)-cGMP signal transduction pathway is impaired in different cardiovascular diseases, including pulmonary hypertension, heart failure and arterial hypertension. Riociguat is a novel stimulator of soluble guanylate cyclase (sGC). However, little is known about the effects of sGC stimulators in experimental models of hypertension. We thus investigated the cardio-renal protective effects of riociguat in low- renin and high-renin rat models of hypertension. Methods The vasorelaxant effect of riociguat was tested in vitro on isolated saphenous artery rings of normal and nitrate tolerant rabbits. The cardiovascular in-vivo effects of sGC stimulation were evaluated in hypertensive renin-transgenic rats treated with the nitric oxide-synthase inhibitor N- nitro-L-arginine methyl ester (L-NAME) (high-renin model) and in rats with 5/6 nephrectomy (low-renin model). Results In both animal models, riociguat treatment improved survival and normalized blood pressure. Moreover, in the L-NAME study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight and lower cardiac interstitial fibrosis, and reduced renal target organ damage as indicated by lower plasma creatinine and urea, less glomerulosclerosis and less renal interstitial fibrosis. In the 5/6 nephrectomy study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight, lower myocyte diameter and lower arterial media/lumen ratio, and reduced renal target organ damage as indicated by improved creatinine clearance and less renal interstitial fibrosis. Conclusion We demonstrate for the first time that the novel sGC stimulator riociguat shows in two independent models of hypertension a potent protection against cardiac and renal target organ damage. J Hypertens 28: 1666-1675 (c) 2010 Wolters Kluwer Health vertical bar Lippincott Williams \& Wilkins.}, language = {en} } @article{HorikoshiYaghootkarMookKanamorietal.2013, author = {Horikoshi, Momoko and Yaghootkar, Hanieh and Mook-Kanamori, Dennis O. and Sovio, Ulla and Taal, H. Rob and Hennig, Branwen J. and Bradfield, Jonathan P. and St Pourcain, Beate and Evans, David M. and Charoen, Pimphen and Kaakinen, Marika and Cousminer, Diana L. and Lehtimaki, Terho and Kreiner-Moller, Eskil and Warrington, Nicole M. and Bustamante, Mariona and Feenstra, Bjarke and Berry, Diane J. and Thiering, Elisabeth and Pfab, Thiemo and Barton, Sheila J. and Shields, Beverley M. and Kerkhof, Marjan and van Leeuwen, Elisabeth M. and Fulford, Anthony J. and Kutalik, Zoltan and Zhao, Jing Hua and den Hoed, Marcel and Mahajan, Anubha and Lindi, Virpi and Goh, Liang-Kee and Hottenga, Jouke-Jan and Wu, Ying and Raitakari, Olli T. and Harder, Marie N. and Meirhaeghe, Aline and Ntalla, Ioanna and Salem, Rany M. and Jameson, Karen A. and Zhou, Kaixin and Monies, Dorota M. and Lagou, Vasiliki and Kirin, Mirna and Heikkinen, Jani and Adair, Linda S. and Alkuraya, Fowzan S. and Al-Odaib, Ali and Amouyel, Philippe and Andersson, Ehm Astrid and Bennett, Amanda J. and Blakemore, Alexandra I. F. and Buxton, Jessica L. and Dallongeville, Jean and Das, Shikta and de Geus, Eco J. C. and Estivill, Xavier and Flexeder, Claudia and Froguel, Philippe and Geller, Frank and Godfrey, Keith M. and Gottrand, Frederic and Groves, Christopher J. and Hansen, Torben and Hirschhorn, Joel N. and Hofman, Albert and Hollegaard, Mads V. and Hougaard, David M. and Hyppoenen, Elina and Inskip, Hazel M. and Isaacs, Aaron and Jorgensen, Torben and Kanaka-Gantenbein, Christina and Kemp, John P. and Kiess, Wieland and Kilpelainen, Tuomas O. and Klopp, Norman and Knight, Bridget A. and Kuzawa, Christopher W. and McMahon, George and Newnham, John P. and Niinikoski, Harri and Oostra, Ben A. and Pedersen, Louise and Postma, Dirkje S. and Ring, Susan M. and Rivadeneira, Fernando and Robertson, Neil R. and Sebert, Sylvain and Simell, Olli and Slowinski, Torsten and Tiesler, Carla M. T. and Toenjes, Anke and Vaag, Allan and Viikari, Jorma S. and Vink, Jacqueline M. and Vissing, Nadja Hawwa and Wareham, Nicholas J. and Willemsen, Gonneke and Witte, Daniel R. and Zhang, Haitao and Zhao, Jianhua and Wilson, James F. and Stumvoll, Michael and Prentice, Andrew M. and Meyer, Brian F. and Pearson, Ewan R. and Boreham, Colin A. G. and Cooper, Cyrus and Gillman, Matthew W. and Dedoussis, George V. and Moreno, Luis A. and Pedersen, Oluf and Saarinen, Maiju and Mohlke, Karen L. and Boomsma, Dorret I. and Saw, Seang-Mei and Lakka, Timo A. and Koerner, Antje and Loos, Ruth J. F. and Ong, Ken K. and Vollenweider, Peter and van Duijn, Cornelia M. and Koppelman, Gerard H. and Hattersley, Andrew T. and Holloway, John W. and Hocher, Berthold and Heinrich, Joachim and Power, Chris and Melbye, Mads and Guxens, Monica and Pennell, Craig E. and Bonnelykke, Klaus and Bisgaard, Hans and Eriksson, Johan G. and Widen, Elisabeth and Hakonarson, Hakon and Uitterlinden, Andre G. and Pouta, Anneli and Lawlor, Debbie A. and Smith, George Davey and Frayling, Timothy M. and McCarthy, Mark I. and Grant, Struan F. A. and Jaddoe, Vincent W. V. and Jarvelin, Marjo-Riitta and Timpson, Nicholas J. and Prokopenko, Inga and Freathy, Rachel M.}, title = {New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism}, series = {Nature genetics}, volume = {45}, journal = {Nature genetics}, number = {1}, publisher = {Nature Publ. Group}, address = {New York}, organization = {MAGIC, Early Growth Genetics EGG}, issn = {1061-4036}, doi = {10.1038/ng.2477}, pages = {76 -- U115}, year = {2013}, abstract = {Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood(1). Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits(2). In an expanded genome-wide association metaanalysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.}, language = {en} } @article{Hocher2014, author = {Hocher, Berthold}, title = {More than genes: the advanced fetal programming hypothesis}, series = {Journal of reproductive immunology : the international journal for experimental and clinical reproductive immunobiology}, volume = {104}, journal = {Journal of reproductive immunology : the international journal for experimental and clinical reproductive immunobiology}, publisher = {Elsevier}, address = {Clare}, issn = {0165-0378}, doi = {10.1016/j.jri.2014.03.001}, pages = {8 -- 11}, year = {2014}, abstract = {Many lines of data, initial epidemiologic studies as well as subsequent extensive experimental studies, indicate that early-life events play a powerful role in influencing later suceptibility to certain chronic diseases. Such events might be over- or undernutrition, exposure to environmental toxins, but also changes in hormones, in particular stress hormones. Typically, those events are triggered by the environmental challenges of the mother. However, recent studies have shown that paternal environmental or nutritional factors affect the phenotype of the offspring as well. The maternal and paternal environmental factors act on the phenotype of the offspring via epigenetic modification of its genome. The advanced fetal programming hypothesis proposes an additional non-environmentally driven mechanism: maternal and also paternal genes may influence the maturating sperm, the oocyte, and later the embryo/fetus, leading to their epigenetic alteration. Thus, the observed phenotype of the offspring may be altered by maternal/paternal genes independent of the fetal genome. Meanwhile, several independent association studies in humans dealing with metabolic and neurological traits also suggest that maternal genes might affect the offspring phenotype independent of the transmission of that particular gene to the offspring. Considering the implications of this hypothesis, some conclusions drawn from transgenic or knockout animal models and based on the causality between a genetic alteration and a phenotype, need to be challenged. Possible implications for the development, diagnostic and therapy of human genetic diseases have to be investigated. (C) 2014 Elsevier Ireland Ltd. All rights reserved.}, language = {en} } @article{HocherOberthuerSlowinskietal.2013, author = {Hocher, Berthold and Oberth{\"u}r, Dominik and Slowinski, Torsten and Querfeld, Uwe and Sch{\"a}fer, Franz and Doyon, Anke and Tepel, Martin and Roth, Heinz J. and Gr{\"o}n, Hans J. and Reichetzeder, Christoph and Betzel, Christian and Armbruster, Franz Paul}, title = {Modeling of Oxidized PTH (oxPTH) and Non-oxidized PTH (n-oxPTH) Receptor Binding and Relationship of Oxidized to Non-Oxidized PTH in Children with Chronic Renal Failure, Adult Patients on Hemodialysis and Kidney Transplant Recipients}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, volume = {37}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, number = {4-5}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000350149}, pages = {240 -- 251}, year = {2013}, abstract = {Background: The biological properties of oxidized and non-oxidized PTH are substantially different. Oxidized PTH (oxPTH) loses its PTH receptor-stimulating properties, whereas non-oxidized PTH (n-oxPTH) is a full agonist of the receptor. This was described in more than 20 well published studies in the 1970(s) and 80(s). However, PTH oxidation has been ignored during the development of PTH assays for clinical use so far. Even the nowadays used third generation assay systems do not consider oxidation of PTH. We recently developed an assay to differentiate between oxPTH and n-oxPTH. In the current study we established normal values for this assay system. Furthermore, we compare the ratio of oxPTH to n-oxPTH in different population with chronic renal failure: 620 children with renal failure stage 2-4 of the 4C study, 342 adult patients on dialysis, and 602 kidney transplant recipients. In addition, we performed modeling of the interaction of either oxPTH or n-oxPTH with the PTH receptor using biophysical structure approaches. Results: The children had the highest mean as well as maximum n-oxPTH concentrations as compared to adult patients (both patients on dialysis as well as kidney transplant recipients). The relationship between oxPTH and n-oxPTH of individual patients varied substantially in all three populations with renal impairment. The analysis of n-oxPTH in 89 healthy control subjects revealed that n-oxPTH concentrations in patient with renal failure were higher as compared to healthy adult controls (2.25-fold in children with renal failure, 1.53-fold in adult patients on dialysis, and 1.56-fold in kidney transplant recipients, respectively). Computer assisted biophysical structure modeling demonstrated, however, minor sterical- and/or electrostatic changes in oxPTH and n-oxPTH. This indicated that PTH oxidation may induce refolding of PTH and hence alters PTH-PTH receptor interaction via oxidation induced three-dimensional structure alteration of PTH. Conclusion: A huge proportion of circulating PTH measured by current state-of-the-art assay systems is oxidized and thus not biologically active. The relationship between oxPTH and n-oxPTH of individual patients varied substantially. Non-oxidized PTH concentrations are 1.5 - 2.25 fold higher in patients with renal failure as compared to health controls. Measurements of n-oxPTH may reflect the hormone status more precise. The iPTH measures describes most likely oxidative stress in patients with renal failure rather than the PTH hormone status. This, however, needs to be demonstrated in further clinical studies.}, language = {en} } @article{HasanvonWebskyReichetzederetal.2019, author = {Hasan, Ahmed Abdallah Abdalrahman Mohamed and von Websky, Karoline and Reichetzeder, Christoph and Tsuprykov, Oleg and Gaballa, Mohamed Mahmoud Salem Ahmed and Guo, Jingli and Zeng, Shufei and Delic, Denis and Tammen, Harald and Klein, Thomas and Kleuser, Burkhard and Hocher, Berthold}, title = {Mechanisms of GLP-1 receptor-independent renoprotective effects of the dipeptidyl peptidase type 4 inhibitor linagliptin in GLP-1 receptor knockout mice with 5/6 nephrectomy}, series = {Kidney international : official journal of the International Society of Nephrology}, volume = {95}, journal = {Kidney international : official journal of the International Society of Nephrology}, number = {6}, publisher = {Elsevier}, address = {New York}, issn = {0085-2538}, doi = {10.1016/j.kint.2019.01.010}, pages = {1373 -- 1388}, year = {2019}, abstract = {Dipeptidyl peptidase type 4 (DPP-4) inhibitors were reported to have beneficial effects in experimental models of chronic kidney disease. The underlying mechanisms are not completely understood. However, these effects could be mediated via the glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP1R) pathway. Here we investigated the renal effects of the DPP-4 inhibitor linagliptin in Glp1r-/- knock out and wild-type mice with 5/6 nephrectomy (5/6Nx). Mice were allocated to groups: sham + wild type + placebo; 5/6Nx+ wild type + placebo; 5/6Nx+ wild type + linagliptin; sham + knock out+ placebo; 5/6Nx + knock out+ placebo; 5/6Nx + knock out+ linagliptin. 5/6Nx caused the development of renal interstitial fibrosis, significantly increased plasma cystatin C and creatinine levels and suppressed renal gelatinase/collagenase, matrix metalloproteinase-1 and -13 activities; effects counteracted by linagliptin treatment in wildtype and Glp1r-/- mice. Two hundred ninety-eight proteomics signals were differentially regulated in kidneys among the groups, with 150 signals specific to linagliptin treatment as shown by mass spectrometry. Treatment significantly upregulated three peptides derived from collagen alpha-1(I), thymosin beta 4 and heterogeneous nuclear ribonucleoprotein Al (HNRNPA1) and significantly downregulated one peptide derived from Y box binding protein-1 (YB-1). The proteomics results were further confirmed using western blot and immunofluorescence microscopy. Also, 5/6Nx led to significant up-regulation of renal transforming growth factor-beta 1 and pSMAD3 expression in wild type mice and linagliptin significantly counteracted this up-regulation in wild type and GIplr-/- mice. Thus, the renoprotective effects of linagliptin cannot solely be attributed to the GLP-1/GLP1R pathway, highlighting the importance of other signaling pathways (collagen I homeostasis, HNRNPA1,YB-1,thymosin beta 4 and TGF-beta 1) influenced by DPP-4 inhibition.}, language = {en} } @article{HocherArmbrusterStoevaetal.2012, author = {Hocher, Berthold and Armbruster, Franz Paul and St{\"o}va, Stanka and Reichetzeder, Christoph and Groen, Hans J{\"u}rgen and Lieker, Ina and Khadzhynov, Dmytro and Slowinski, Torsten and Roth, Heinz J{\"u}rgen}, title = {Measuring Parathyroid Hormone (PTH) in patients with oxidative stress - do we need a fourth generation Parathyroid Hormone assay?}, series = {PLoS one}, volume = {7}, journal = {PLoS one}, number = {7}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0040242}, pages = {10}, year = {2012}, abstract = {Oxidation of PTH at methionine residues results in loss of biological activity. PTH may be oxidized in patients with renal disease. The aim of this study was to develop an assay considering oxidation of PTH. Oxidized hPTH was analyzed by high resolution nano-liquid chromatography coupled to ESI-FTT tandem mass spectrometry (nanoLC-ESI-FT-MS/MS) directly and after proteolytic cleavage. The oxidized hPTH(1-84) sample shows TIC-peaks at 18-20 min and several mass peaks due to mass shifts caused by oxidations. No significant signal for oxidized hPTH(1-84) species after removal of oxidized PTH molecules by a specific column with monoclonal antibodies (MAB) raised against the oxidized hPTH was detectable. By using this column in samples from 18 patients on dialysis we could demonstrate that measured PTH concentrations were substantially lower when considering oxidized forms of PTH. The relationship between PTH concentrations determined directly and those concentrations measured after removal of the oxidized PTH forms varies substantially. In some patients only 7\% of traditionally measured PTH was free of oxidation, whereas in other patients 34\% of the traditionally measured PTH was real intact PTH. In conclusion, a huge but not constant proportion of PTH molecules are oxidized in patients requiring dialysis. Since oxidized PTH is biologically inactive, the currently used methods to detect PTH in daily clinical practice may not adequately reflect PTH-related bone and cardiovascular abnormalities in patients on dialysis.}, language = {en} } @article{ReichetzederChenFoelleretal.2014, author = {Reichetzeder, Christoph and Chen, Hong and Foeller, Michael and Slowinski, Torsten and Li, Jian and Chen, You-Peng and Lang, Florian and Hocher, Berthold}, title = {Maternal vitamin D deficiency and fetal programming - lessons learned from humans and mice}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, volume = {39}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, number = {4}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000355809}, pages = {315 -- 329}, year = {2014}, abstract = {Background/Aims: Cardiovascular disease partially originates from poor environmental and nutritional conditions in early life. Lack of micronutrients like 25 hydroxy vitamin D-3 (25OHD) during pregnancy may be an important treatable causal factor. The present study explored the effect of maternal 25OHD deficiency on the offspring. Methods: We performed a prospective observational study analyzing the association of maternal 25OHD deficiency during pregnancy with birth outcomes considering confounding. To show that vitamin D deficiency may be causally involved in the observed associations, mice were set on either 25OHD sufficient or insufficient diets before and during pregnancy. Growth, glucose tolerance and mortality was analyzed in the F1 generation. Results: The clinical study showed that severe 25OHD deficiency was associated with low birth weight and low gestational age. ANCOVA models indicated that established confounding factors such as offspring sex, smoking during pregnancy and maternal BMI did not influence the impact of 25OHD on birth weight. However, there was a significant interaction between 25OHD and gestational age. Maternal 25OHD deficiency was also independently associated with low APGAR scores 5 minutes postpartum. The offspring of 25OHD deficient mice grew slower after birth, had an impaired glucose tolerance shortly after birth and an increased mortality during follow-up. Conclusions: Our study demonstrates an association between maternal 25OHD and offspring birth weight. The effect of 25OHD on birth weight seems to be mediated by vitamin D controlling gestational age. Results from an animal experiment suggest that gestational 25OHD insufficiency is causally linked to adverse pregnancy outcomes. Since birth weight and prematurity are associated with an adverse cardiovascular outcome in later life, this study emphasizes the need for novel monitoring and treatment guidelines of vitamin D deficiency during pregnancy.}, language = {en} } @article{LiLuReichetzederetal.2016, author = {Li, Jian and Lu, Yong Ping and Reichetzeder, Christoph and Kalk, Philipp and Kleuser, Burkhard and Adamski, Jerzy and Hocher, Berthold}, title = {Maternal PCaaC38:6 is Associated With Preterm Birth - a Risk Factor for Early and Late Adverse Outcome of the Offspring}, series = {Journal of European public policy}, volume = {41}, journal = {Journal of European public policy}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000443428}, pages = {250 -- 257}, year = {2016}, abstract = {Background/Aims: Preterm birth (PTB) and low birth weight (LBW) significantly influence mortality and morbidity of the offspring in early life and also have long-term consequences in later life. A better understanding of the molecular mechanisms of preterm birth could provide new insights regarding putative preventive strategies. Metabolomics provides a powerful analytic tool to readout complex interactions between genetics, environment and health and may serve to identify relevant biomarkers. In this study, the association between 163 targeted maternal blood metabolites and gestational age was investigated in order to find candidate biomarkers for PTB. Methods: Five hundred twenty-three women were included into this observational study. Maternal blood was obtained before delivery. The concentration of 163 maternal serum metabolites was measured by flow injection tandem mass spectrometry. To find putative biomarkers for preterm birth, a three-step analysis was designed: bivariate correlation analysis followed by multivariable regression analysis and a comparison of mean values among gestational age groups. Results: Bivariate correlation analysis showed that 2 acylcarnitines (C16:2, C2), 1 amino acids (xLeu), 8 diacyl-PCs (PCaaC36:4, PCaaC38:4, PCaaC38:5, PCaaC38:6, PCaaC40:4, PCaaC40:5, PCaaC40:6, PCaaC42:4), and 1 Acylalkyl-PCs (PCaeC40:5) were inversely correlated with gestational age. Multivariable regression analysis confounded for PTB history, maternal body mass index (BMI) before pregnancy, systolic blood pressure at the third trimester, and maternal body weight at the third trimester, showed that the diacyl-PC PCaaC38:6 was the only metabolite inversely correlated with gestational age. Conclusions: Maternal blood concentrations of PCaaC38:6 are independently associated with gestational age. (C) 2016 The Author(s) Published by S. Karger AG, Basel}, language = {en} } @article{HocherHaumannRahnenfuehreretal.2016, author = {Hocher, Berthold and Haumann, Hannah and Rahnenf{\"u}hrer, Jan and Reichetzeder, Christoph and Kalk, Philipp and Pfab, Thiemo and Tsuprykov, Oleg and Winter, Stefan and Hofmann, Ute and Li, Jian and P{\"u}schel, Gerhard Paul and Lang, Florian and Schuppan, Detlef and Schwab, Matthias and Schaeffeler, Elke}, title = {Maternal eNOS deficiency determines a fatty liver phenotype of the offspring in a sex dependent manner}, series = {Epigenetics : the official journal of the DNA Methylation Society}, volume = {11}, journal = {Epigenetics : the official journal of the DNA Methylation Society}, publisher = {Routledge, Taylor \& Francis Group}, address = {Philadelphia}, issn = {1559-2294}, doi = {10.1080/15592294.2016.1184800}, pages = {539 -- 552}, year = {2016}, abstract = {Maternal environmental factors can impact on the phenotype of the offspring via the induction of epigenetic adaptive mechanisms. The advanced fetal programming hypothesis proposes that maternal genetic variants may influence the offspring's phenotype indirectly via epigenetic modification, despite the absence of a primary genetic defect. To test this hypothesis, heterozygous female eNOS knockout mice and wild type mice were bred with male wild type mice. We then assessed the impact of maternal eNOS deficiency on the liver phenotype of wild type offspring. Birth weight of male wild type offspring born to female heterozygous eNOS knockout mice was reduced compared to offspring of wild type mice. Moreover, the offspring displayed a sex specific liver phenotype, with an increased liver weight, due to steatosis. This was accompanied by sex specific differences in expression and DNA methylation of distinct genes. Liver global DNA methylation was significantly enhanced in both male and female offspring. Also, hepatic parameters of carbohydrate metabolism were reduced in male and female offspring. In addition, male mice displayed reductions in various amino acids in the liver. Maternal genetic alterations, such as partial deletion of the eNOS gene, can affect liver metabolism of wild type offspring without transmission of the intrinsic defect. This occurs in a sex specific way, with more detrimental effects in females. This finding demonstrates that a maternal genetic defect can epigenetically alter the phenotype of the offspring, without inheritance of the defect itself. Importantly, these acquired epigenetic phenotypic changes can persist into adulthood.}, language = {en} } @article{WarringtonBeaumontHorikoshietal.2019, author = {Warrington, Nicole and Beaumont, Robin and Horikoshi, Momoko and Day, Felix R. and Helgeland, {\O}yvind and Laurin, Charles and Bacelis, Jonas and Peng, Shouneng and Hao, Ke and Feenstra, Bjarke and Wood, Andrew R. and Mahajan, Anubha and Tyrrell, Jessica and Robertson, Neil R. and Rayner, N. William and Qiao, Zhen and Moen, Gunn-Helen and Vaudel, Marc and Marsit, Carmen and Chen, Jia and Nodzenski, Michael and Schnurr, Theresia M. and Zafarmand, Mohammad Hadi and Bradfield, Jonathan P. and Grarup, Niels and Kooijman, Marjolein N. and Li-Gao, Ruifang and Geller, Frank and Ahluwalia, Tarunveer Singh and Paternoster, Lavinia and Rueedi, Rico and Huikari, Ville and Hottenga, Jouke-Jan and Lyytik{\"a}inen, Leo-Pekka and Cavadino, Alana and Metrustry, Sarah and Cousminer, Diana L. and Wu, Ying and Thiering, Elisabeth Paula and Wang, Carol A. and Have, Christian Theil and Vilor-Tejedor, Natalia and Joshi, Peter K. and Painter, Jodie N. and Ntalla, Ioanna and Myhre, Ronny and Pitk{\"a}nen, Niina and van Leeuwen, Elisabeth M. and Joro, Raimo and Lagou, Vasiliki and Richmond, Rebecca C. and Espinosa, Ana and Barton, Sheila J. and Inskip, Hazel M. and Holloway, John W. and Santa-Marina, Loreto and Estivill, Xavier and Ang, Wei and Marsh, Julie A. and Reichetzeder, Christoph and Marullo, Letizia and Hocher, Berthold and Lunetta, Kathryn L. and Murabito, Joanne M. and Relton, Caroline L. and Kogevinas, Manolis and Chatzi, Leda and Allard, Catherine and Bouchard, Luigi and Hivert, Marie-France and Zhang, Ge and Muglia, Louis J. and Heikkinen, Jani and Morgen, Camilla S. and van Kampen, Antoine H. C. and van Schaik, Barbera D. C. and Mentch, Frank D. and Langenberg, Claudia and Scott, Robert A. and Zhao, Jing Hua and Hemani, Gibran and Ring, Susan M. and Bennett, Amanda J. and Gaulton, Kyle J. and Fernandez-Tajes, Juan and van Zuydam, Natalie R. and Medina-Gomez, Carolina and de Haan, Hugoline G. and Rosendaal, Frits R. and Kutalik, Zolt{\´a}n and Marques-Vidal, Pedro and Das, Shikta and Willemsen, Gonneke and Mbarek, Hamdi and M{\"u}ller-Nurasyid, Martina and Standl, Marie and Appel, Emil V. R. and Fonvig, Cilius Esmann and Trier, Caecilie and van Beijsterveldt, Catharina E. M. and Murcia, Mario and Bustamante, Mariona and Bon{\`a}s-Guarch, S{\´i}lvia and Hougaard, David M. and Mercader, Josep M. and Linneberg, Allan and Schraut, Katharina E. and Lind, Penelope A. and Medland, Sarah Elizabeth and Shields, Beverley M. and Knight, Bridget A. and Chai, Jin-Fang and Panoutsopoulou, Kalliope and Bartels, Meike and S{\´a}nchez, Friman and Stokholm, Jakob and Torrents, David and Vinding, Rebecca K. and Willems, Sara M. and Atalay, Mustafa and Chawes, Bo L. and Kovacs, Peter and Prokopenko, Inga and Tuke, Marcus A. and Yaghootkar, Hanieh and Ruth, Katherine S. and Jones, Samuel E. and Loh, Po-Ru and Murray, Anna and Weedon, Michael N. and T{\"o}njes, Anke and Stumvoll, Michael and Michaelsen, Kim Fleischer and Eloranta, Aino-Maija and Lakka, Timo A. and van Duijn, Cornelia M. and Kiess, Wieland and Koerner, Antje and Niinikoski, Harri and Pahkala, Katja and Raitakari, Olli T. and Jacobsson, Bo and Zeggini, Eleftheria and Dedoussis, George V. and Teo, Yik-Ying and Saw, Seang-Mei and Montgomery, Grant W. and Campbell, Harry and Wilson, James F. and Vrijkotte, Tanja G. M. and Vrijheid, Martine and de Geus, Eco J. C. N. and Hayes, M. Geoffrey and Kadarmideen, Haja N. and Holm, Jens-Christian and Beilin, Lawrence J. and Pennell, Craig E. and Heinrich, Joachim and Adair, Linda S. and Borja, Judith B. and Mohlke, Karen L. and Eriksson, Johan G. and Widen, Elisabeth E. and Hattersley, Andrew T. and Spector, Tim D. and Kaehoenen, Mika and Viikari, Jorma S. and Lehtimaeki, Terho and Boomsma, Dorret I. and Sebert, Sylvain and Vollenweider, Peter and Sorensen, Thorkild I. A. and Bisgaard, Hans and Bonnelykke, Klaus and Murray, Jeffrey C. and Melbye, Mads and Nohr, Ellen A. and Mook-Kanamori, Dennis O. and Rivadeneira, Fernando and Hofman, Albert and Felix, Janine F. and Jaddoe, Vincent W. V. and Hansen, Torben and Pisinger, Charlotta and Vaag, Allan A. and Pedersen, Oluf and Uitterlinden, Andre G. and Jarvelin, Marjo-Riitta and Power, Christine and Hypponen, Elina and Scholtens, Denise M. and Lowe, William L. and Smith, George Davey and Timpson, Nicholas J. and Morris, Andrew P. and Wareham, Nicholas J. and Hakonarson, Hakon and Grant, Struan F. A. and Frayling, Timothy M. and Lawlor, Debbie A. and Njolstad, Pal R. and Johansson, Stefan and Ong, Ken K. and McCarthy, Mark I. and Perry, John R. B. and Evans, David M. and Freathy, Rachel M.}, title = {Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors}, series = {Nature genetics}, volume = {51}, journal = {Nature genetics}, number = {5}, publisher = {Nature Publ. Group}, address = {New York}, organization = {EGG Consortium}, issn = {1061-4036}, pages = {804 -- +}, year = {2019}, abstract = {Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.}, language = {en} } @article{EspeRailaHenzeetal.2013, author = {Espe, Katharina M. and Raila, Jens and Henze, Andrea and Blouin, Katja and Schneider, Andreas and Schmiedeke, Daniel and Krane, Vera and Pilz, Stefan and Schweigert, Florian J. and Hocher, Berthold and Wanner, Christoph and Drechsler, Christiane}, title = {Low plasma alpha-tocopherol concentrations and adverse clinical outcomes in diabetic hemodialysis patients}, series = {Clinical journal of the American Society of Nephrology}, volume = {8}, journal = {Clinical journal of the American Society of Nephrology}, number = {3}, publisher = {American Society of Nephrology}, address = {Washington}, organization = {German Diabet \& Dialysis Study Inv}, issn = {1555-9041}, doi = {10.2215/CJN.04880511}, pages = {452 -- 458}, year = {2013}, abstract = {Background and objectives Trials with the antioxidant vitamin E have failed to show benefit in the general population. Considering the different causes of death in ESRD, this study investigated the association between plasma concentrations of alpha-tocopherol and specific clinical outcomes in diabetic hemodialysis patients. Design, settings, participants, \& measurements In 1046 diabetic hemodialysis patients (participants of the German Diabetes and Dialysis Study), alpha-tocopherol was measured in plasma by reversed-phase HPLC. By Cox regression analyses, hazard ratios were determined for prespecified end points according to baseline plasma alpha-tocopherol levels: sudden death (n=134), myocardial infarction (n=172), stroke (n=89), combined cardiovascular events (n=398), fatal infection (n=107), and all-cause mortality (n=508). Results Patients had a mean age of 66 8 years, and mean plasma alpha-tocopherol level was 22.8+/-9.6 mu mol/L. Levels of alpha-tocopherol were highly correlated to triglycerides (r=0.63, P<0.001). Patients in the lowest alpha-tocopherol quartile had (in unadjusted analyses) a 79\% higher risk of stroke and a 31\% higher risk of all-cause mortality compared with patients in the highest quartile. The associations were attenuated after adjustment for confounders (hazard ratio(stroke)=1.56, 95\% confidence interval=0.75-3.25; hazard ratio(mortality)=1.22, 95\% confidence interval=0.89-1.69, respectively). There was no association between alpha-tocopherol and myocardial infarction, sudden death, or infectious death. Conclusions Plasma alpha-tocopherol concentrations were not independently associated with cardiovascular outcomes, infectious deaths, or all-cause mortality in diabetic hemodialysis patients. The lack of association can partly be explained by a confounding influence of malnutrition, which should be considered in the planning of trials to reduce cardiovascular risk in dialysis patients.}, language = {en} } @article{LuZengChenetal.2013, author = {Lu, Yong-Ping and Zeng, De-Ying and Chen, You-Peng and Liang, Xu-Jing and Xu, Jie-Ping and Huang, Si-Min and Lai, Zhi-Wei and Wen, Wang-Rong and von Websky, Karoline and Hocher, Berthold}, title = {Low birth weight is associated with lower respiratory tract infections in children with hand, foot, and mouth disease}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {59}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {9-10}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2012.120725}, pages = {985 -- 992}, year = {2013}, abstract = {Background: Low birth weight (LBW) might be a risk factor for acquiring lower respiratory tract infections (LRTIs) associated with disease related complications in early childhood. HFMD, a frequent viral infection in southern China, is a leading cause of lower respiratory tract infections in children. We analyzed whether LBW is a risk factor for children with HFMD to develop lower respiratory tract infections. Methods: A total of 298 children with HFMD, admitted to a hospital in Qingyuan city, Guangdong province, were recruited. Demographic data and clinical parameters such as serum glucose level and inflammatory markers including peripheral white blood cell count, serum C-reactive protein, and erythrocyte sedimentation rate were routinely collected on admission. Birth weight data were derived from birth records. Results: Mean birth weight (BW) was 167 g lower in patients with HFMD and LRTIs as compared to patients with solely HFMD (p = 0.022) and the frequency of birth weight below the tenth percentile was significantly higher in patients with HFMD and LRTIs (p = 0.002). Conclusions: The results of the study show that low birth weight is associated with a higher incidence of lower respiratory tract infections in young children with HFMD.}, language = {en} } @article{LiWangSchlemmetal.2011, author = {Li, Jian and Wang, Zi-Neng and Schlemm, Ludwig and Pfab, Thiemo and Xiao, Xiao-Min and Chen, You-Peng and Hocher, Berthold}, title = {Low birth weight and elevated head-to-abdominal circumference ratio are associated with elevated fetal glycated serum protein concentrations}, series = {Journal of hypertension}, volume = {29}, journal = {Journal of hypertension}, number = {9}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {0263-6352}, doi = {10.1097/HJH.0b013e328349a2e6}, pages = {1712 -- 1718}, year = {2011}, abstract = {Objective To analyze the association between low birth weight, head-to-abdominal circumference ratio, and insulin resistance in early life. Method and results Glycated serum proteins (GSPs) were quantified at delivery in 612 Chinese mother/child pairs serving as a surrogate of maternal and fetal glycemia. Differential ultrasound examination of the fetal's body (head circumference, biparietal diameter, pectoral diameter, abdominal circumference, and femur length) was done in average 1 week prior to delivery. Multivariable regression analysis considering gestational age at delivery, the child's sex, maternal BMI, maternal age at delivery, maternal body weight, and pregnancyinduced hypertension revealed that fetal GSP was inversely associated with birth weight (R(2) = 0.416; P < 0.001). Fetal GSP was furthermore positively associated with the head-to-abdominal circumference ratio, whereas the maternal GSP was negatively correlated with the offspring's head-to-abdominal circumference ratio (R(2) = 0.285; P = 0.010 and R(2) = 0.261; P = 0.020, respectively). The increased head-to-abdominal circumference ratio in newborns with higher fetal GSP is mainly due to a reduced abdominal circumference rather than reduced growth of the brain. Conclusion The disproportional intrauterine growth is in line with the concept of so-called brain sparing, a mechanism maintaining the intrauterine growth of the brain at the expense of trunk growth. Our data suggest that the low birth weight phenotype, linked to cardiovascular diseases like hypertension in later life, might be a phenotype of disproportional intrauterine growth retardation and early life insulin resistance.}, language = {en} } @article{NairHocherVerkaartetal.2012, author = {Nair, Anil V. and Hocher, Berthold and Verkaart, Sjoerd and van Zeeland, Femke and Pfab, Thiemo and Slowinski, Torsten and Chen, You-Peng and Schlingmann, Karl Peter and Schaller, Andre and Gallati, Sabina and Bindels, Rene J. and Konrad, Martin and H{\"o}nderop, Joost G.}, title = {Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy}, series = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {109}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {28}, publisher = {National Acad. of Sciences}, address = {Washington}, issn = {0027-8424}, doi = {10.1073/pnas.1113811109}, pages = {11324 -- 11329}, year = {2012}, abstract = {Hypomagnesemia affects insulin resistance and is a risk factor for diabetes mellitus type 2 (DM2) and gestational diabetes mellitus (GDM). Two single nucleotide polymorphisms (SNPs) in the epithelial magnesium channel TRPM6 ((VI)-I-1393, (KE)-E-1584) were predicted to confer susceptibility for DM2. Here, we show using patch clamp analysis and total internal reflection fluorescence microscopy, that insulin stimulates TRPM6 activity via a phosphoinositide 3-kinase and Rac1-mediated elevation of cell surface expression of TRPM6. Interestingly, insulin failed to activate the genetic variants TRPM6 ((VI)-I-1393) and TRPM6((KE)-E-1584), which is likely due to the inability of the insulin signaling pathway to phosphorylate TRPM6(T-1391) and TRPM6(S-1583). Moreover, by measuring total glycosylated hemoglobin (TGH) in 997 pregnant women as a measure of glucose control, we demonstrate that TRPM6((VI)-I-1393) and TRPM6((KE)-E-1584) are associated with higher TGH and confer a higher likelihood of developing GDM. The impaired response of TRPM6((VI)-I-1393) and TRPM6((KE)-E-1584) to insulin represents a unique molecular pathway leading to GDM where the defect is located in TRPM6.}, language = {en} } @article{WangLiZhangetal.2018, author = {Wang, Guang and Li, Pei-zhi and Zhang, Shi-yao and Zhong, Shan and Chu, Chang and Zeng, Shufei and Yan, Yu and Cheng, Xin and Chuai, Manli and Hocher, Berthold and Yang, Xuesong}, title = {Lipopolysaccharides (LPS) Induced Angiogenesis During Chicken Embryogenesis is Abolished by Combined ETA/ETB Receptor Blockade}, series = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, volume = {48}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, number = {5}, publisher = {Karger}, address = {Basel}, issn = {1015-8987}, doi = {10.1159/000492547}, pages = {2084 -- 2090}, year = {2018}, abstract = {Background/Aims: Angiogenesis plays a key role during embryonic development. The vascular endothelin (ET) system is involved in the regulation of angiogenesis. Lipopolysaccharides (LPS) could induce angiogenesis. The effects of ET blockers on baseline and LPS-stimulated angiogenesis during embryonic development remain unknown so far. Methods: The blood vessel density (BVD) of chorioallantoic membranes (CAMs), which were treated with saline (control), LPS, and/or BQ123 and the ETB blocker BQ788, were quantified and analyzed using an IPP 6.0 image analysis program. Moreover, the expressions of ET-1, ET-2, ET3, ET receptor A (ETRA), ET receptor B (ETRB) and VEGFR2 mRNA during embryogenesis were analyzed by semi-quantitative RT-PCR. Results: All components of the ET system are detectable during chicken embryogenesis. LPS increased angiogenesis substantially. This process was completely blocked by the treatment of a combination of the ETA receptor blockers-BQ123 and the ETB receptor blocker BQ788. This effect was accompanied by a decrease in ETRA, ETRB, and VEGFR2 gene expression. However, the baseline angiogenesis was not affected by combined ETA/ETB receptor blockade. Conclusion: During chicken embryogenesis, the LPS-stimulated angiogenesis, but not baseline angiogenesis, is sensitive to combined ETA/ETB receptor blockade.}, language = {en} } @article{GroopCooperPerkovicetal.2017, author = {Groop, Per-Henrik and Cooper, Mark E. and Perkovic, Vlado and Hocher, Berthold and Kanasaki, Keizo and Haneda, Masakazu and Schernthaner, Guntram and Sharma, Kumar and Stanton, Robert C. and Toto, Robert and Cescutti, Jessica and Gordat, Maud and Meinicke, Thomas and Koitka-Weber, Audrey and Thiemann, Sandra and von Eynatten, Maximilian}, title = {Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction}, series = {Diabetes obesity \& metabolism : a journal of pharmacology and therapeutics}, volume = {19}, journal = {Diabetes obesity \& metabolism : a journal of pharmacology and therapeutics}, number = {11}, publisher = {Wiley}, address = {Hoboken}, issn = {1462-8902}, doi = {10.1111/dom.13041}, pages = {1610 -- 1619}, year = {2017}, abstract = {Aims: The MARLINA-T2D study (ClinicalTrials. gov, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard-of-care in individuals with type 2 diabetes and albuminuria. Methods: A total of 360 individuals with type 2 diabetes, HbA1c 6.5\% to 10.0\% (48-86 mmol/ mol), estimated glomerular filtration rate (eGFR) >= 30 mL/min/1.73 m(2) and urinary albumin-tocreatinine ratio (UACR) 30-3000 mg/g despite single agent renin-angiotensin-system blockade were randomized to double-blind linagliptin (n = 182) or placebo (n = 178) for 24 weeks. The primary and key secondary endpoints were change from baseline in HbA1c at week 24 and time-weighted average of percentage change from baseline in UACR over 24 weeks, respectively. Results: Baseline mean HbA1c and geometric mean (gMean) UACR were 7.8\% +/- 0.9\% (62.2 +/- 9.6 mmol/mol) and 126 mg/g, respectively; 73.7\% and 20.3\% of participants had microalbuminuria or macroalbuminuria, respectively. After 24 weeks, the placebo-adjusted mean change in HbA1c from baseline was -0.60\% (-6.6 mmol/mol) (95\% confidence interval [CI], -0.78 to -0.43 [-8.5 to -4.7 mmol/mol]; P <.0001). The placebo-adjusted gMean for time-weighted average of percentage change in UACR from baseline was -6.0\% (95\% CI, -15.0 to 3.0; P =.1954). The adverse-event profile, including renal safety and change in eGFR, was similar between the linagliptin and placebo groups. Conclusions: In individuals at early stages of diabetic kidney disease, linagliptin significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo-adjusted eGFR. Detection of clinically relevant renal effects of linagliptin may require longer treatment, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular haemodynamics.}, language = {en} } @article{LiWangChenetal.2012, author = {Li, Jian and Wang, Zi-Neng and Chen, You-Peng and Dong, Yun-Peng and Shuai, Han-Lin and Xiao, Xiao-Min and Reichetzeder, Christoph and Hocher, Berthold}, title = {Late gestational maternal serum cortisol is inversely associated with fetal brain growth}, series = {Neuroscience \& biobehavioral reviews : official journal of the International Behavioral Neuroscience Society}, volume = {36}, journal = {Neuroscience \& biobehavioral reviews : official journal of the International Behavioral Neuroscience Society}, number = {3}, publisher = {Elsevier}, address = {Oxford}, issn = {0149-7634}, doi = {10.1016/j.neubiorev.2011.12.006}, pages = {1085 -- 1092}, year = {2012}, abstract = {To analyze the association between fetal brain growth and late gestational blood serum cortisol in normal pregnancy.Blood total cortisol was quantified at delivery in 432 Chinese mother/child pairs. Key inclusion criteria of the cohort were: no structural anomalies of the newborn, singleton pregnancy, no alcohol abuse, no drug abuse or history of smoking no hypertensive disorders and no impairment of glucose tolerance and no use of steroid medication during pregnancy. Differential ultrasound examination of the fetal body was done in early (gestational day 89.95 +/- 7.31), middle (gestational day 160.17 16.12) and late pregnancy (gestational day 268.89 +/- 12.42). Newborn's cortisol was not correlated with any of the ultrasound measurements during pregnancy nor with birth weight. Multivariable regression analysis, considering timing of the ultrasound examination, the child's sex, maternal BMI, maternal age, maternal body weight at delivery, the timing of cortisol measurement and maternal uterine contraction states, revealed that maternal serum total cortisol was significantly negative correlated with ultrasound parameters describing the fetal brain: late biparietal diameter (R-2 =0.512, p =0.009), late head circumference (R-2 = 0.498, p= 0.001), middle biparietal diameter (R-2= 0.819, p = 0.013), middle cerebellum transverse diameter R-2 = 0.76, p= 0.014) and early biparietal diameter(R-2 = 0.819, p = 0.013). The same analysis revealed that birth weight as well as ultrasound parameters such as abdominal circumference and femur length were not correlated to maternal cortisol levels. In conclusion, our study demonstrates that maternal cortisol secretion within physiological ranges may be inversely correlated to fetal brain growth but not to birth weight. It remains to be demonstrated whether maternal cortisol secretion negatively influencing fetal brain growth translates to adverse neurological outcomes in later life.}, language = {en} } @article{BaerFegerFajoletal.2018, author = {B{\"a}r, Ludmilla and Feger, Martina and Fajol, Abul and Klotz, Lars-Oliver and Zeng, Shufei and Lang, Florian and Hocher, Berthold and F{\"o}ller, Michael}, title = {Insulin suppresses the production of fibroblast growth factor 23 (FGF23)}, series = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {115}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {22}, publisher = {National Acad. of Sciences}, address = {Washington}, issn = {0027-8424}, doi = {10.1073/pnas.1800160115}, pages = {5804 -- 5809}, year = {2018}, abstract = {Fibroblast growth factor 23 (FGF23) is produced by bone cells and regulates renal phosphate and vitamin D metabolism, as well as causing left ventricular hypertrophy. FGF23 deficiency results in rapid aging, whereas high plasma FGF23 levels are found in several disorders, including kidney or cardiovascular diseases. Regulators of FGF23 production include parathyroid hormone (PTH), calcitriol, dietary phosphate, and inflammation. We report that insulin and insulin-like growth factor 1 (IGF1) are negative regulators of FGF23 production. In UMR106 osteoblast-like cells, insulin and IGF1 down-regulated FGF23 production by inhibiting the transcription factor forkhead box protein O1 (FOXO1) through phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB)/Akt signaling. Insulin deficiency caused a surge in the serum FGF23 concentration in mice, which was reversed by administration of insulin. In women, a highly significant negative correlation between FGF23 plasma concentration and increase in plasma insulin level following an oral glucose load was found. Our results provide strong evidence that insulin/IGF1dependent PI3K/PKB/Akt/FOXO1 signaling is a powerful suppressor of FGF23 production in vitro as well as in mice and in humans.}, language = {en} } @article{ReichetzederPutraPfabetal.2016, author = {Reichetzeder, Christoph and Putra, S. E. Dwi and Pfab, T. and Slowinski, T. and Neuber, Corinna and Kleuser, Burkhard and Hocher, Berthold}, title = {Increased global placental DNA methylation levels are associated with gestational diabetes}, series = {Clinical epigenetics}, volume = {8}, journal = {Clinical epigenetics}, publisher = {BioMed Central}, address = {London}, issn = {1868-7083}, doi = {10.1186/s13148-016-0247-9}, pages = {10}, year = {2016}, abstract = {Background: Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes. It is known that GDM is associated with an altered placental function and changes in placental gene regulation. More recent studies demonstrated an involvement of epigenetic mechanisms. So far, the focus regarding placental epigenetic changes in GDM was set on gene-specific DNA methylation analyses. Studies that robustly investigated placental global DNA methylation are lacking. However, several studies showed that tissue-specific alterations in global DNA methylation are independently associated with type 2 diabetes. Thus, the aim of this study was to characterize global placental DNA methylation by robustly measuring placental DNA 5-methylcytosine (5mC) content and to examine whether differences in placental global DNA methylation are associated with GDM. Methods: Global DNA methylation was quantified by the current gold standard method, LC-MS/MS. In total, 1030 placental samples were analyzed in this single-center birth cohort study. Results: Mothers with GDM displayed a significantly increased global placental DNA methylation (3.22 +/- 0.63 vs. 3.00 +/- 0.46 \%; p = 0.013; +/- SD). Bivariate logistic regression showed a highly significant positive correlation between global placental DNA methylation and the presence of GDM (p = 0.0009). Quintile stratification according to placental DNA 5mC levels revealed that the frequency of GDM was evenly distributed in quintiles 1-4 (2.9-5.3 \%), whereas the frequency in the fifth quintile was significantly higher (10.7 \%; p = 0.003). Bivariate logistic models adjusted for maternal age, BMI, ethnicity, recurrent miscarriages, and familiar diabetes predisposition clearly demonstrated an independent association between global placental DNA hypermethylation and GDM. Furthermore, an ANCOVA model considering known predictors of DNA methylation substantiated an independent association between GDM and placental DNA methylation. Conclusions: This is the first study that employed a robust quantitative assessment of placental global DNA methylation in over a thousand placental samples. The study provides large scale evidence that placental global DNA hypermethylation is associated with GDM, independent of established risk factors.}, language = {en} } @article{SunHuangMengetal.2012, author = {Sun, Sheng-Yun and Huang, Jin and Meng, Min-Jie and Lu, Jia-Hai and Hocher, Berthold and Liu, Kang-Li and Yang, Qin-He and Zhu, Xiao-Feng}, title = {Improvement of lipid profile and reduction of body weight by Shan He Jian Fei Granules in high fat diet-induced obese rats}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {1-2}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, pages = {81 -- 87}, year = {2012}, abstract = {Background: The goal was to study lipid profiles (TG, TC, LDL, HDL), effects on serum leptin, and fat tissue adiponectin, and resistin as well as body weight effects of Shan He Jian Fei Granules (SHJFG) in rats on a high fat diet. Methods: Rats were randomly divided into five groups: normal control group fed with normal fat diet, rats on high fat diet receiving low dosage, middle dosage, high dosage of Shan He Jian Fei Granules (SHJFG) as well as a high fat diet group receiving placebo. Rats were treated for 8 weeks. Body weight and naso-anal length of each rat were recorded and Lee's index was calculated. Serum TG, TC, LDL, HDL and leptin concentrations were analyzed. The gene expressions of adiponectin and resistin in adipose tissues were tested by RT-PCR. Results: Compared to the high-fat diet group, body weights, Lee's indexes, weight of fat tissues and serum TG, TC, LDL and leptin of SHJFG groups significantly decreased (p<0.05), whereas mRNA expressions of adiponectin and resistin of SHJFG groups significantly increased (p<0.05). Conclusions: SHJFG could significantly lower body weight and serum TG, TC, and LDL of obese rats. The effects of SHJFG in lowering leptin synthesis and raising mRNA expression of adiponectin and resistin in fat tissues may act as part of the mechanisms in lowering body weight of obese rats. Further studies are needed to demonstrate whether SHJFG may also reduce overall cardiovascular morbidity and mortality like other lipid lowering drugs.}, language = {en} } @article{vonWebskyHasanReichetzederetal.2018, author = {von Websky, Karoline and Hasan, Ahmed Abdallah Abdalrahman Mohamed and Reichetzeder, Christoph and Tsuprykov, Oleg and Hocher, Berthold}, title = {Impact of vitamin D on pregnancy-related disorders and on offspring outcome}, series = {The Journal of Steroid Biochemistry and Molecular Biology}, volume = {180}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, publisher = {Elsevier}, address = {Oxford}, issn = {0960-0760}, doi = {10.1016/j.jsbmb.2017.11.008}, pages = {51 -- 64}, year = {2018}, abstract = {Observational studies from all over the world continue to find high prevalence rates of vitamin D insufficiency and deficiency in many populations, including pregnant women. Beyond its classical function as a regulator of calcium and phosphate metabolism, vitamin D elicits numerous effects in the human body. Current evidence highlights a vital role of vitamin D in mammalian gestation. During pregnancy, adaptations in maternal vitamin D metabolism lead to a physiologic increase of vitamin D levels, mainly because of an increased renal production, although other potential sources like the placenta are being discussed. A sufficient supply of mother and child with calcium and vitamin D during pregnancy ensures a healthy bone development of the fetus, whereas lack of either of these nutrients can lead to the development of rickets in the child. Moreover, vitamin D insufficiency during pregnancy has consistently been associated with adverse maternal and neonatal pregnancy outcomes. In multitudinous studies, low maternal vitamin D status was associated with a higher risk for pre-eclampsia, gestational diabetes mellitus and other gestational diseases. Likewise, several negative consequences for the fetus have been reported, including fetal growth restriction, increased risk of preterm birth and a changed susceptibility for later-life diseases. However, study results are diverging and causality has not been proven so far. Meta-analyses on the relationship between maternal vitamin D status and pregnancy outcomes revealed a wide heterogeneity of studied populations and the applied methodology in vitamin D assessment. Until today, clinical guidelines for supplementation cannot be based on high-quality evidence and it is not clear if the required intake for pregnant women differs from non-pregnant women. Long-term safety data of vitamin D supplementation in pregnant women has not been established and overdosing of vitamin D might have unfavorable effects, especially in mothers and newborns with mutations of genes involved in vitamin D metabolism. Reliable data from large observational and interventional randomized control trials are urgently needed as a basis for any detailed and safe recommendations for supplementation in the general population and, most importantly, in pregnant women. This is of utmost importance, as ensuring a sufficient vitamin D-supply of mother and child implies a great potential for the prevention of birth complications and development of diseases.}, language = {en} } @article{EspeRailaHenzeetal.2011, author = {Espe, Katharina M. and Raila, Jens and Henze, Andrea and Krane, Vera and Schweigert, Florian J. and Hocher, Berthold and Wanner, Christoph and Drechsler, Christiane}, title = {Impact of vitamin A on clinical outcomes in haemodialysis patients}, series = {Nephrology, dialysis, transplantation}, volume = {26}, journal = {Nephrology, dialysis, transplantation}, number = {12}, publisher = {Oxford Univ. Press}, address = {Oxford}, organization = {German Diabetes \& Dialysis Study I}, issn = {0931-0509}, doi = {10.1093/ndt/gfr171}, pages = {4054 -- U583}, year = {2011}, abstract = {Background. Patients on maintenance haemodialysis treatment experience an excessive risk of cardiovascular disease and mortality. The vitamin A concentration is known to be higher in these patients compared to the general population where elevated vitamin A concentrations are associated with adverse outcome. The impact of vitamin A on morbidity and mortality in end-stage renal disease patients is controversial and is the topic of this study. Methods. We analysed plasma retinol and retinol-binding protein 4 (RBP4) in 1177 diabetic haemodialysis patients, who participated in the German Diabetes and Dialysis Study (median follow-up 4 years). By Cox regression analyses hazard ratios (HRs) were determined for pre-specified, adjudicated end points according to baseline concentrations. Results. Patients had a mean age of 66 +/- 8 years, mean retinol and RBP4 concentrations of 3.28 (0.71-7.44) and 4.02 (1.28-10.1) mu mol/L, respectively. Patients with retinol concentrations in the first quartile (<2.6 mu mol/L) had an almost 2-fold increased risk of all-cause mortality compared to patients of the fourth quartile [>3.9 mu mol/L; HR 1.81, 95\% confidence interval (CI) 1.43-2.30]. There was a strong association between low retinol and the risk of sudden cardiac death (SCD, HR 2.22, 95\% CI 1.41-3.50) and fatal infection (HR 2.19, 95\% CI 1.26-3.82). Patients with RBP4 concentrations in the lowest quartile (<3.0 mu mol/L) were more likely to die of any cause (HR 1.43, 95\% CI 1.14-1.80), experience SCD (HR 1.97, 95\% CI 1.28-3.03) and cardiovascular events (HR 1.43, 95\% CI 1.10-1.85). Conclusion. This large cohort study shows a strong association of low retinol and RBP4 concentrations with SCD and all-cause mortality in diabetic haemodialysis patients.}, language = {en} } @article{FischerKempeLeibrocketal.2010, author = {Fischer, Stephanie S. and Kempe, Daniela S. and Leibrock, Christina B. and Rexhepaj, Rexhep and Siraskar, Balasaheb and Boini, Krishna M. and Ackermann, Teresa F. and Foeller, Michael and Hocher, Berthold and Rosenblatt, Kevin P. and Kuro-o, Makoto and Lang, Florian}, title = {Hyperaldosteronism in Klotho-deficient mice}, issn = {1931-857X}, doi = {10.1152/ajprenal.00233.2010}, year = {2010}, abstract = {Klotho is a membrane protein participating in the inhibitory effect of FGF23 on the formation of 1,25- dihydroxyvitamin-D-3 [1,25(OH)(2)D-3]. It participates in the regulation of renal tubular phosphate reabsorption and stimulates renal tubular Ca2+ reabsorption. Klotho hypomorphic mice (klotho(hm)) suffer from severe growth deficit, rapid aging, and early death, events largely reversed by a vitamin D-deficient diet. The present study explored the role of Klotho deficiency in mineral and electrolyte metabolism. To this end, klothohm mice and wild-type mice (klotho(+/+)) were subjected to a normal (D+) or vitamin D-deficient (D-) diet or to a vitamin D-deficient diet for 4 wk and then to a normal diet (D-/+). At the age of 8 wk, body weight was significantly lower in klotho(hm)D(+) mice than in klotho(+/ +)D(+) mice, klotho(hm)D(-) mice, and klotho(hm)D(-/+) mice. Plasma concentrations of 1,25(OH)(2)D-3, adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), and aldosterone were significantly higher in klotho(hm)D(+) mice than in klotho(+/+)D(+) mice. Plasma volume was significantly smaller in klotho(hm)D(-/+) mice, and plasma urea, Ca2+, phosphate and Na+, but not K+ concentrations were significantly higher in klotho(hm)D(+) mice than in klotho(+/+)D(+) mice. The differences were partially abrogated by a vitamin D-deficient diet. Moreover, the hyperaldosteronism was partially reversed by Ca2+-deficient diet. Ussing chamber experiments revealed a marked increase in amiloride-sensitive current across the colonic epithelium, pointing to enhanced epithelial sodium channel (ENaC) activity. A salt-deficient diet tended to decrease and a salt-rich diet significantly increased the life span of klotho(hm)D(+) mice. In conclusion, the present observation disclose that the excessive formation of 1,25(OH)(2)D-3 in Klotho-deficient mice results in extracellular volume depletion, which significantly contributes to the shortening of life span.}, language = {en} } @article{GaoWangZhangetal.2018, author = {Gao, Lin-rui and Wang, Guang and Zhang, Jing and Li, Shuai and Chuai, Manli and Bao, Yongping and Hocher, Berthold and Yang, Xuesong}, title = {High salt-induced excess reactive oxygen species production resulted in heart tube malformation during gastrulation}, series = {Journal of Cellular Physiology}, volume = {233}, journal = {Journal of Cellular Physiology}, number = {9}, publisher = {Wiley}, address = {Hoboken}, issn = {0021-9541}, doi = {10.1002/jcp.26528}, pages = {7120 -- 7133}, year = {2018}, abstract = {An association has been proved between high salt consumption and cardiovascular mortality. In vertebrates, the heart is the first functional organ to be formed. However, it is not clear whether high-salt exposure has an adverse impact on cardiogenesis. Here we report high-salt exposure inhibited basement membrane breakdown by affecting RhoA, thus disturbing the expression of Slug/E-cadherin/N-cadherin/Laminin and interfering with mesoderm formation during the epithelial-mesenchymal transition(EMT). Furthermore, the DiI(+) cell migration trajectory in vivo and scratch wound assays in vitro indicated that high-salt exposure restricted cell migration of cardiac progenitors, which was caused by the weaker cytoskeleton structure and unaltered corresponding adhesion junctions at HH7. Besides, down-regulation of GATA4/5/6, Nkx2.5, TBX5, and Mef2c and up-regulation of Wnt3a/-catenin caused aberrant cardiomyocyte differentiation at HH7 and HH10. High-salt exposure also inhibited cell proliferation and promoted apoptosis. Most importantly, our study revealed that excessive reactive oxygen species(ROS)generated by high salt disturbed the expression of cardiac-related genes, detrimentally affecting the above process including EMT, cell migration, differentiation, cell proliferation and apoptosis, which is the major cause of malformation of heart tubes.}, language = {en} } @article{LiangHuangLietal.2014, author = {Liang, Xu-Jing and Huang, Si-Min and Li, Jian-Ping and Zhu, Xian-Nv and Lu, Yong-Ping and Hocher, Berthold and Chen, You-Peng}, title = {Hepatic impairment induced by scrub typhus is associated with new onset of renal dysfunction}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {60}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {1}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2013.121203}, pages = {63 -- 68}, year = {2014}, abstract = {Background: Scrub typhus is a potentially fatal infectious disease caused by Orientia tsutsugamushi. There is little attention given to hepatic impairment in the adults with scrub typhus. This study investigated the incidence and the prognostic implications of hepatic impairment in patients with scrub typhus. Methods: We retrospectively reviewed a total of 143 adult patients with scrub typhus who were admitted between January 1999 and December 2010 in Guangdong province, China. The patients were divided into three groups, e.g., normal, mild, and moderate to severe groups based on the elevated serum ALT and/or total bilirubin levels. Furthermore, clinical characteristics and prognosis of the patient groups were compared. Results: 109 patients (76.2\%) had abnormal liver function. Among the patients with hepatic impairment 45 cases (31.4\%), 54 cases (37.8\%), and 10 cases (7.0\%) had mild, moderate, and severe hepatic damage, respectively. The moderate to severe hepatic impairment group had higher levels of serum creatinine compared with that of normal hepatic function. The incidence of new onset of renal dysfunction - defined as peak serum creatinine >= 176 mu mol/L during hospital stay with no evidence of renal disease prior hospitalization - was 0\% in the mild hepatic impairment group, 8.9\% in the moderate hepatic impairment group, and 21.9\% in the severe hepatic impairment group, (p = 0.005 for trend). Additionally, the patients with hepatic impairment (n = 109) had higher incidences of episodes of thrombocytopenia (45.9\% vs. 8.82\%, p < 0.001), hypoalbuminemia (50.5\% vs. 11.8\%, p < 0.001), new onset of renal dysfunction (16.5\% vs. 0.0\%, p = 0.011), and electrocardiogram abnormality (28.4\% vs. 8.82\%, p = 0.019) than the patients without hepatic impairment. Conclusions: The degree of hepatic impairment induced by scrub typhus is associated with new onset of renal dysfunction.}, language = {en} } @article{ReichetzedervonWebskyTsuprykovetal.2017, author = {Reichetzeder, Christoph and von Websky, Karoline and Tsuprykov, Oleg and Samarin, Azadeh Mohagheghi and Falke, Luise Gabriele and Putra, Sulistyo Emantoko Dwi and Hasan, Ahmed Abdallah Abdalrahman Mohamed and Antonenko, Viktoriia and Curato, Caterina and Rippmann, Joerg and Klein, Thomas and Hocher, Berthold}, title = {Head-to-head comparison of structurally unrelated dipeptidyl peptidase 4 inhibitors in the setting of renal ischemia reperfusion injury}, series = {British journal of pharmacology : journal of The British Pharmacological Society}, volume = {174}, journal = {British journal of pharmacology : journal of The British Pharmacological Society}, publisher = {Wiley}, address = {Hoboken}, issn = {0007-1188}, doi = {10.1111/bph.13822}, pages = {2273 -- 2286}, year = {2017}, abstract = {BACKGROUND AND PURPOSE Results regarding protective effects of dipeptidyl peptidase 4 (DPP4) inhibitors in renal ischaemia-reperfusion injury (IRI) are conflicting. Here we have compared structurally unrelated DPP4 inhibitors in a model of renal IRI. EXPERIMENTAL APPROACH IRI was induced in uninephrectomizedmale rats by renal artery clamping for 30 min. The shamgroup was uninephrectomized but not subjected to IRI. DPP4 inhibitors or vehicle were given p. o. once daily on three consecutive days prior to IRI: linagliptin (1.5 mg.kg(-1).day(-1)), vildagliptin (8mg.kg(-1).day(-1)) and sitagliptin (30 mg.kg(-1).day(-1)). An additional group received sitagliptin until study end (before IRI: 30 mg.kg(-1).day(-1); after IRI: 15mg.kg(-1).day(-1)). KEY RESULTS Plasma-active glucagon-like peptide type 1 (GLP(-1)) increased threefold to fourfold in all DPP4 inhibitor groups 24 h after IRI. Plasma cystatin C, a marker of GFR, peaked 48 h after IRI. Compared with the placebo group, DPP4 inhibition did not reduce increased plasma cystatin C levels. DPP4 inhibitors ameliorated histopathologically assessed tubular damage with varying degrees of drug-specific efficacies. Renal osteopontin expression was uniformly reduced by all DPP4 inhibitors. IRI-related increased renal cytokine expression was not decreased by DPP4 inhibition. Renal DPP4 activity at study end was significantly inhibited in the linagliptin group, but only numerically reduced in the prolonged/dose-adjusted sitagliptin group. Active GLP(-1) plasma levels at study end were increased only in the prolonged/dose-adjusted sitagliptin treatment group. CONCLUSIONS AND IMPLICATIONS In rats with renal IRI, DPP4 inhibition did not alter plasma cystatin C, a marker of glomerular function, but may protect against tubular damage.}, language = {en} } @article{LuTsuprykovVignonZellwegeretal.2016, author = {Lu, Yong Ping and Tsuprykov, Oleg and Vignon-Zellweger, Nicolas and Heiden, Susi and Hocher, Berthold}, title = {Global Overexpression of ET-1 Decreases Blood Pressure - A Systematic Review and Meta-Analysis of ET-1 Transgenic Mice}, series = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {41}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000450567}, pages = {770 -- 780}, year = {2016}, abstract = {Background/Aims: ET-1 has independent effects on blood pressure regulation in vivo, it is involved in tubular water and salt excretion, promotes constriction of smooth muscle cells, modulates sympathetic nerve activity, and activates the liberation of nitric oxide. To determine the net effect of these partially counteracting mechanisms on blood pressure, a systematic meta-analysis was performed. Methods: Based on the principles of Cochrane systematic reviews, we searched in major literature databases - MEDLINE (PubMed), Embase, Google Scholar, and the China Biological Medicine Database (CBM-disc) - for articles relevant to the topic of the blood pressure phenotype of endothelin-1 transgenic (ET-1+/+) mice from January 1, 1988 to March 31, 2016. Review Manager Version 5.0 (Rev-Man 5.0) software was applied for statistical analysis. In total thirteen studies reported blood pressure data. Results: The meta-analysis of blood pressure data showed that homozygous ET-1 transgenic mice (ET-1+/+ mice) had a significantly lower blood pressure as compared to WT mice (mean difference:-2.57 mmHg, 95\% CI: -4.98 similar to -0.16, P = 0.04), with minimal heterogeneity (P = 0.86). A subgroup analysis of mice older than 6 months revealed that the blood pressure difference between ET-1+/+ mice and WT mice was even more pronounced (mean difference: -6.19 mmHg, 95\% CI: -10.76 similar to -1.62, P = 0.008), with minimal heterogeneity (P = 0.91). Conclusion: This meta-analysis provides robust evidence that global ET-1 overexpression in mice lowers blood pressure in an age-dependent manner. Older ET-1+/+ mice have a somewhat more pronounced reduction of blood pressure. (C) 2016 The Author(s) Published by S. Karger AG, Basel}, language = {en} } @article{BeaumontWarringtonCavadinoetal.2018, author = {Beaumont, Robin N. and Warrington, Nicole M. and Cavadino, Alana and Tyrrell, Jessica and Nodzenski, Michael and Horikoshi, Momoko and Geller, Frank and Myhre, Ronny and Richmond, Rebecca C. and Paternoster, Lavinia and Bradfield, Jonathan P. and Kreiner-Moller, Eskil and Huikari, Ville and Metrustry, Sarah and Lunetta, Kathryn L. and Painter, Jodie N. and Hottenga, Jouke-Jan and Allard, Catherine and Barton, Sheila J. and Espinosa, Ana and Marsh, Julie A. and Potter, Catherine and Zhang, Ge and Ang, Wei and Berry, Diane J. and Bouchard, Luigi and Das, Shikta and Hakonarson, Hakon and Heikkinen, Jani and Helgeland, Oyvind and Hocher, Berthold and Hofman, Albert and Inskip, Hazel M. and Jones, Samuel E. and Kogevinas, Manolis and Lind, Penelope A. and Marullo, Letizia and Medland, Sarah E. and Murray, Anna and Murray, Jeffrey C. and Njolstad, Pal R. and Nohr, Ellen A. and Reichetzeder, Christoph and Ring, Susan M. and Ruth, Katherine S. and Santa-Marina, Loreto and Scholtens, Denise M. and Sebert, Sylvain and Sengpiel, Verena and Tuke, Marcus A. and Vaudel, Marc and Weedon, Michael N. and Willemsen, Gonneke and Wood, Andrew R. and Yaghootkar, Hanieh and Muglia, Louis J. and Bartels, Meike and Relton, Caroline L. and Pennell, Craig E. and Chatzi, Leda and Estivill, Xavier and Holloway, John W. and Boomsma, Dorret I. and Montgomery, Grant W. and Murabito, Joanne M. and Spector, Tim D. and Power, Christine and Jarvelin, Marjo-Ritta and Bisgaard, Hans and Grant, Struan F. A. and Sorensen, Thorkild I. A. and Jaddoe, Vincent W. and Jacobsson, Bo and Melbye, Mads and McCarthy, Mark I. and Hattersley, Andrew T. and Hayes, M. Geoffrey and Frayling, Timothy M. and Hivert, Marie-France and Felix, Janine F. and Hypponen, Elina and Lowe, William L. and Evans, David M. and Lawlor, Debbie A. and Feenstra, Bjarke and Freathy, Rachel M.}, title = {Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics}, series = {Human molecular genetics}, volume = {27}, journal = {Human molecular genetics}, number = {4}, publisher = {Oxford Univ. Press}, address = {Oxford}, organization = {Early Growth Genetics EGG}, issn = {0964-6906}, doi = {10.1093/hmg/ddx429}, pages = {742 -- 756}, year = {2018}, abstract = {Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P< 5 x 10(-8). In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.}, language = {en} } @article{RokutanSuckowvonHaehlingetal.2012, author = {Rokutan, Hirofumi and Suckow, Christian and von H{\"a}hling, Stephan and Strassburg, Sabine and Bockmeyer, Barbara and D{\"o}hner, Wolfram and Waller, Christiane and Bauersachs, Johann and von Websky, Karoline and Hocher, Berthold and Anker, Stefan D. and Springer, Jochen}, title = {Furosemide induces mortality in a rat model of chronic heart failure}, series = {International journal of cardiology}, volume = {160}, journal = {International journal of cardiology}, number = {1}, publisher = {Elsevier}, address = {Clare}, issn = {0167-5273}, doi = {10.1016/j.ijcard.2011.03.005}, pages = {20 -- 25}, year = {2012}, abstract = {Objectives: In an experimental heart failure model, we tested the hypothesis that furosemide causes excess mortality. Background: Post-hoc analysis of large clinical heart failure trails revealed that furosemide treatment might be associated with worsening of morbidity and even mortality in heart failure patients. Methods and results: Myocardial infarction was induced in 7 +/- 1 week old male Wistar rats by ligation of the left coronary artery. In study 1, animals were randomly assigned to treatment with furosemide (10 mg/kg/d via drinking water, n = 33) or placebo (n = 33) starting 18 days after surgery. In study 2, animals received furosemide from day 18 and were then randomized to ongoing treatment with either furosemide only (n = 38) or furosemide plus ACE-inhibitor Ramipril (1 mg/kg/d, n = 38) starting on day 42. In study 1 survival rate in the furosemide group was lower than in the placebo group (hazard ratio {HR} 3.39, 95\% confidence interval {CI} 1.14 to 10.09, p = 0.028). The furosemide group had a lower body weight (-6\%, p = 0.028) at the end of the study and a higher sclerosis index of the glomeruli (+9\%, p=0.026) than the placebo group. Wet lung weight, infarct size, and cardiac function were similar between the groups. In study 2, the furosemide group had a higher mortality rate than the furosemide + ramipril group (HR 4.55, 95\% CI 2.0 to 10.0, p = 0.0003). Conclusion: In our rat model of heart failure furosemide, provided at a standard dose, was associated with increased mortality. This increased mortality could be prevented by additional administration of an ACE-inhibitor.}, language = {en} } @article{LiLuTsuprykovetal.2018, author = {Li, Jian and Lu, Yong-Ping and Tsuprykov, Oleg and Hasan, Ahmed Abdallah Abdalrahman Mohamed and Reichetzeder, Christoph and Tian, Mei and Zhang, Xiao Li and Zhang, Qin and Sun, Guo-Ying and Guo, Jingli and Gaballa, Mohamed Mahmoud Salem Ahmed and Peng, Xiao-Ning and Lin, Ge and Hocher, Berthold}, title = {Folate treatment of pregnant rat dams abolishes metabolic effects in female offspring induced by a paternal pre-conception unhealthy diet}, series = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)}, volume = {61}, journal = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)}, number = {8}, publisher = {Springer}, address = {New York}, issn = {0012-186X}, doi = {10.1007/s00125-018-4635-x}, pages = {1862 -- 1876}, year = {2018}, abstract = {Aims/hypothesis Paternal high-fat diet prior to mating programmes impaired glucose tolerance in female offspring. We examined whether the metabolic consequences in offspring could be abolished by folate treatment of either the male rats before mating or the corresponding female rats during pregnancy. Methods Male F0 rats were fed either control diet or high-fat, high-sucrose and high-salt diet (HFSSD), with or without folate, before mating. Male rats were mated with control-diet-fed dams. After mating, the F0 dams were fed control diet with or without folate during pregnancy.}, language = {en} } @article{LuReichetzederPrehnetal.2018, author = {Lu, Yong-Ping and Reichetzeder, Christoph and Prehn, Cornelia and von Websky, Karoline and Slowinski, Torsten and Chen, You-Peng and Yin, Liang-Hong and Kleuser, Burkhard and Yang, Xue-Song and Adamski, Jerzy and Hocher, Berthold}, title = {Fetal serum metabolites are independently associated with Gestational diabetes mellitus}, series = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, volume = {45}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, number = {2}, publisher = {Karger}, address = {Basel}, issn = {1015-8987}, doi = {10.1159/000487119}, pages = {625 -- 638}, year = {2018}, abstract = {Background/Aims: Gestational diabetes (GDM) might be associated with alterations in the metabolomic profile of affected mothers and their offspring. Until now, there is a paucity of studies that investigated both, the maternal and the fetal serum metabolome in the setting of GDM. Mounting evidence suggests that the fetus is not just passively affected by gestational disease but might play an active role in it. Metabolomic studies performed in maternal blood and fetal cord blood could help to better discern distinct fetal from maternal disease interactions. Methods: At the time of birth, serum samples from mothers and newborns (cord blood samples) were collected and screened for 163 metabolites utilizing tandem mass spectrometry. The cohort consisted of 412 mother/child pairs, including 31 cases of maternal GDM. Results: An initial non-adjusted analysis showed that eight metabolites in the maternal blood and 54 metabolites in the cord blood were associated with GDM. After Benjamini-Hochberg (BH) procedure and adjustment for confounding factors for GDM, fetal phosphatidylcholine acyl-alkyl C 32:1 and proline still showed an independent association with GDM. Conclusions: This study found metabolites in cord blood which were associated with GDM, even after adjustment for established risk factors of GDM. To the best of our knowledge, this is the first study demonstrating an independent association between fetal serum metabolites and maternal GDM. Our findings might suggest a potential effect of the fetal metabolome on maternal GDM. (c) 2018 The Author(s) Published by S. Karger AG, Basel}, language = {en} } @article{ChenLuLietal.2014, author = {Chen, You-Peng and Lu, Yong-Ping and Li, Jian and Liu, Zhi-Wei and Chen, Wen-Jing and Liang, Xu-Jing and Chen, Xin and Wen, Wang-Rong and Xiao, Xiao-Min and Reichetzeder, Christoph and Hocher, Berthold}, title = {Fetal and maternal angiotensin (1-7) are associated with preterm birth}, series = {Journal of hypertension}, volume = {32}, journal = {Journal of hypertension}, number = {9}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {0263-6352}, doi = {10.1097/HJH.0000000000000251}, pages = {1833 -- 1841}, year = {2014}, abstract = {Background: Recent studies show that preterm birth is associated with hypertension in later life. The renin-angiotensin system (RAS) during pregnancy influences fetal growth and development. In the current study, we investigated the impact of fetal as well as maternal angiotensin (1-7) [Ang (1-7)] and angiotensin II (Ang II) plasma concentrations on the risk of preterm birth. Methods: Three hundred and nine pregnant women were prospectively included into the study. The pregnant women were divided into two groups, for example, preterm birth of lower than 37 gestational weeks (n = 17) and full-term birth of 37 gestational weeks or more (n = 292). Maternal and neonatal plasma Ang (1-7) and Ang II concentrations were analyzed at birth from maternal venous blood and umbilical cord blood, respectively. Risk factors for premature birth were determined by multiple logistic regression analysis. Results: Fetal and maternal plasma Ang (1-7) concentrations in the preterm group were lower than those of the term group fetal Ang (1-7) preterm birth: 486.15 +/- 337.34 ng/l and fetal Ang (1-7) term birth: 833.84 +/- 698.12 ng/l and maternal Ang (1-7) preterm birth: 399.86 +/- 218.93 ng/l; maternal Ang (1-7) term birth: 710.34 +/- 598.22 ng/l. Multiple logistic regression analysis considering confounding factors revealed that preeclampsia (P < 0.001), premature rupture of membranes (P = 0.001), lower concentration of maternal Ang (1-7) (P = 0.013) and fetal plasma Ang (1-7) (P = 0.032) were independently associated with preterm birth. We could furthermore demonstrate that the maternal Ang (1-7)/Ang II ratio is independently associated with gestational hypertension or preeclampsia, factors causing preterm birth. Conclusions: Lower concentrations of maternal and fetal Ang (1-7) are independently associated with preterm birth - a risk factor of hypertension in later life.}, language = {en} } @article{KalkSharkovskaKashinaetal.2011, author = {Kalk, Philipp and Sharkovska, Yuliya and Kashina, Elena and von Websky, Karoline and Relle, Katharina and Pfab, Thiemo and Alter, Markus L. and Guillaume, Philippe and Provost, Daniel and Hoffmann, Katrin and Fischer, Yvan and Hocher, Berthold}, title = {Endothelin-Converting Enzyme/Neutral Endopeptidase Inhibitor SLV338 Prevents Hypertensive Cardiac Remodeling in a Blood Pressure-Independent Manner}, series = {HYPERTENSION}, volume = {57}, journal = {HYPERTENSION}, number = {4}, publisher = {LIPPINCOTT WILLIAMS \& WILKINS}, address = {PHILADELPHIA}, issn = {0194-911X}, doi = {10.1161/HYPERTENSIONAHA.110.163972}, pages = {755 -- 763}, year = {2011}, abstract = {Hypertensive heart disease is a major contributor to cardiovascular mortality. Endothelin is a potent vasoconstrictive and profibrotic mediator produced by the endothelin-converting enzyme (ECE), whereas natriuretic peptides, degraded by the neutral endopeptidase (NEP), have diuretic, vasodilatory, and antifibrotic properties. Thus, combined ECE/NEP inhibition may halt hypertensive cardiac remodeling. This study examined effects of SLV338, a novel ECE/NEP inhibitor, on cardiac protection in experimental renovascular hypertension (2-kidney, 1-clip [2K1C]). Male rats were allocated to 5 groups: sham-operated rats, untreated animals with 2K1C, 2K1C animals treated with oral SLV338 (30 and 100 mg/kg per day), and 2K1C animals treated with oral losartan (20 mg/kg per day). Treatment duration was 12 weeks. Blood pressure was assessed every 4 weeks. At study end, hearts were taken for histology/computer-aided histomorphometry/immunohistochemistry. Pharmacological properties of SLV338 are described. SLV338 is a dual ECE/NEP inhibitor, as demonstrated both in vitro and in vivo. In the 2K1C study, losartan lowered blood pressure by <= 46 mm Hg, whereas both dosages of SLV338 had no effect. However, SLV338 (both dosages) completely normalized cardiac interstitial fibrosis, perivascular fibrosis, myocyte diameter, and media: lumen ratio of cardiac arteries, as did losartan. Cardiac transforming growth factor-beta 1 expression was significantly enhanced in untreated 2K1C rats versus controls, whereas treatment with SLV338 and losartan prevented this effect. Taken together, dual ECE/NEP inhibitor SLV338 prevents cardiac remodeling to the same extent as losartan, but in a blood pressure-independent manner, in a rat model of renovascular hypertension. This effect is at least partially mediated via suppression of cardiac transforming growth factor-beta 1 expression. (Hypertension. 2011;57:755-763.)}, language = {en} } @article{VignonZellwegerRelleKienlenetal.2011, author = {Vignon-Zellweger, Nicolas and Relle, Katharina and Kienlen, Elodie and Alter, Markus L. and Seider, Patrick and Sharkovska, Juliya and Heiden, Susi and Kalk, Philipp and Schwab, Karima and Albrecht-Kuepper, Barbara and Theuring, Franz and Stasch, Johannes-Peter and Hocher, Berthold}, title = {Endothelin-1 overexpression restores diastolic function in eNOS knockout mice}, series = {Journal of hypertension}, volume = {29}, journal = {Journal of hypertension}, number = {5}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {0263-6352}, doi = {10.1097/HJH.0b013e3283450770}, pages = {961 -- 970}, year = {2011}, abstract = {Background The cardiac nitric oxide and endothelin-1 (ET-1) systems are closely linked and play a critical role in cardiac physiology. The balance between both systems is often disturbed in cardiovascular diseases. To define the cardiac effect of excessive ET-1 in a status of nitric oxide deficiency, we compared left ventricular function and morphology in wild-type mice, ET-1 transgenic (ET+/+) mice, endothelial nitric oxide synthase knockout (eNOS(-/-)) mice, and ET(+/+)eNOS(-/-) mice. Methods and results eNOS(-/-) and ET(+/+)eNOS(-/-) mice developed high blood pressure compared with wild-type and ET+/+ mice. Left ventricular catheterization showed that eNOS(-/-) mice, but not ET(+/+)eNOS(-/-), developed diastolic dysfunction characterized by increased end-diastolic pressure and relaxation constant tau. To elucidate the causal molecular mechanisms driving the rescue of diastolic function in ET(+/+)eNOS(-/-) mice, the cardiac proteome was analyzed. Two-dimensional gel electrophoresis coupled to mass spectrometry offers an appropriate hypothesis-free approach. ET-1 overexpression on an eNOS(-/-) background led to an elevated abundance and change in posttranslational state of antioxidant enzymes (e. g., peroxiredoxin-6, glutathione S-transferase mu 2, and heat shock protein beta 7). In contrast to ET(+/+)eNOS(-/-) mice, eNOS(-/-) mice showed an elevated abundance of proteins responsible for sarcomere disassembly (e. g., cofilin-1 and cofilin-2). In ET(+/+)eNOS(-/-) mice, glycolysis was favored at the expense of fatty acid oxidation. Conclusion eNOS(-/-) mice developed diastolic dysfunction; this was rescued by ET-1 transgenic overexpression. This study furthermore suggests that cardiac ET-1 overexpression in case of eNOS deficiency causes specifically the regulation of proteins playing a role in oxidative stress, myocytes contractility, and energy metabolism.}, language = {en} } @article{TsuprykovChaykovskaKretschmeretal.2015, author = {Tsuprykov, Oleg and Chaykovska, Lyubov and Kretschmer, Axel and Stasch, Johannes-Peter and Pfab, Thiemo and Krause-Relle, Katharina and Reichetzeder, Christoph and Kalk, Philipp and Adamski, Jerzy and Hocher, Berthold}, title = {Endothelin-1 overexpression improves renal function in eNOS knockout mice}, series = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, volume = {37}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, number = {4}, publisher = {Karger}, address = {Basel}, issn = {1015-8987}, doi = {10.1159/000438516}, pages = {1474 -- 1490}, year = {2015}, abstract = {Background/Aims: To investigate the renal phenotype under conditions of an activated renal ET-1 system in the status of nitric oxide deficiency, we compared kidney function and morphology in wild-type, ET-1 transgenic (ET+/+), endothelial nitric oxide synthase knockout (eNOS-/-) and ET+/+eNOS-/- mice. Methods: We assessed blood pressure, parameters of renal morphology, plasma cystatin C, urinary protein excretion, expression of genes associated with glomerular filtration barrier and tissue remodeling, and plasma metabolites using metabolomics. Results: eNOS-/- and ET+/+eNOS-/- mice developed hypertension. Osteopontin, albumin and protein excretion were increased in eNOS-/- and restored in ET+/+eNOS-/- animals. All genetically modified mice developed renal interstitial fibrosis and glomerulosclerosis. Genes involved in tissue remodeling (serpinel, TIMP1, Collal, CCL2) were up-regulated in eNOS-/-, but not in ET+/+eNOS-/- mice. Plasma levels of free carnitine and acylcarnitines, amino acids, diacyl phosphatidylcholines, lysophosphatidylcholines and hexoses were descreased in eNOS-/- and were in the normal range in ET+/+eNOS-/- mice. Conclusion: eNOS-/- mice developed renal dysfunction, which was partially rescued by ET-1 overexpression in eNOS-/- mice. The metabolomics results suggest that ET-1 overexpression on top of eNOS knockout is associated with a functional recovery of mitochondria (rescue effect in 13-oxidation of fatty acids) and an increase in antioxidative properties (normalization of monounsaturated fatty acids levels). (C) 2015 The Author(s) Published by S. Karger AG, Basel}, language = {en} } @article{VignonZellwegerRelleRahnenfuehreretal.2014, author = {Vignon-Zellweger, Nicolas and Relle, Katharina and Rahnenfuehrer, Jan and Schwab, Karima and Hocher, Berthold and Theuring, Franz}, title = {Endothelin-1 overexpression and endothelial nitric oxide synthase knock-out induce different pathological responses in the heart of male and female mice}, series = {Life sciences : molecular, cellular and functional basis of therapy}, volume = {118}, journal = {Life sciences : molecular, cellular and functional basis of therapy}, number = {2}, publisher = {Elsevier}, address = {Oxford}, issn = {0024-3205}, doi = {10.1016/j.lfs.2013.12.003}, pages = {219 -- 225}, year = {2014}, abstract = {Aims: The nitric oxide and endothelin systems are key components of a local paracrine hormone network in the heart. We previously reported that diastolic dysfunction observed in mice lacking the endothelial nitric oxide synthase (eNOS-/-) can be prevented by a genetic overexpression of ET-1. Sexual dimorphisms have been reported in both ET-1 and NO systems. Particularly, eNOS-/- mice present sex related phenotypic differences. Main methods: We used the ET-1 transgenic (ET+/+), eNOS-/-, and crossbred ET+/+ eNOS-/- mice, and wild type controls. We measured cardiac function by heart catheterization. Cardiac ventricles were collected for histological and molecular profiling. Key findings: We report here that (i) the level of ET-1 expression in eNOS-/- mice was elevated in males but not in females. (ii) Left ventricular end-diastolic blood pressure was higher in male eNOS-/- mice than in females. (ii) eNOS-/- males but not females developed cardiomyocyte hypertrophy. (iv) Perivascular fibrosis of intra-cardiac arteries developed in female ET+/+ and eNOS-/- mice but not in males. Additionally, (v) the cardiac expression of metalloprotease-9 was higher in eNOS-/- males compared to females. Finally, (vi) cardiac proteome analysis revealed that the protein abundance of the oxidative stress related enzyme superoxide dismutase presented with sexual dimorphism in eNOS-/- and ET+/+ mice. Significance: These results indicate that the cardiac phenotypes of ET-1 transgenic mice and eNOS knockout mice are sex specific. Since both systems are key players in the pathogenesis of cardiovascular diseases, our findings might be important in the context of gender differences in patients with such diseases. (C) 2013 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).}, language = {en} } @article{SchildrothRettigZimmermannKalketal.2011, author = {Schildroth, Janice and Rettig-Zimmermann, Juliane and Kalk, Philipp and Steege, Andreas and Faehling, Michael and Sendeski, Mauricio and Paliege, Alexander and Lai, En Yin and Bachmann, Sebastian and Persson, Pontus B. and Hocher, Berthold and Patzak, Andreas}, title = {Endothelin type A and B receptors in the control of afferent and efferent arterioles in mice}, series = {Nephrology, dialysis, transplantation}, volume = {26}, journal = {Nephrology, dialysis, transplantation}, number = {3}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {0931-0509}, doi = {10.1093/ndt/gfq534}, pages = {779 -- 789}, year = {2011}, abstract = {Background. Endothelin 1 contributes to renal blood flow control and pathogenesis of kidney diseases. The differential effects, however, of endothelin 1 (ET-1) on afferent (AA) and efferent arterioles (EA) remain to be established. Methods. We investigated endothelin type A and B receptor (ETA-R, ETB-R) functions in the control of AA and EA. Arterioles of ETB-R deficient, rescued mice [ETB (-/-)] and wild types [ETB(+/+)] were microperfused. Results. ET-1 constricted AA stronger than EA in ETB (-/-) and ETB(+/+) mice. Results in AA: ET-1 induced similar constrictions in ETB(-/-) and ETB(+/+) mice. BQ-123 (ETA-R antagonist) inhibited this response in both groups. ALA-ET-1 and IRL1620 (ETB-R agonists) had no effect on arteriolar diameter. L-NAME did neither affect basal diameters nor ET-1 responses. Results in EA: ET-1 constricted EA stronger in ETB(+/+) compared to ETB(-/-). BQ-123 inhibited the constriction completely only in ETB(-/-). ALA-ET-1 and IRL1620 constricted only arterioles of ETB(+/+) mice. L-NAME decreased basal diameter in ETB(+/+), but not in ETB(-/-) mice and increased the ET-1 response similarly in both groups. The L-NAME actions indicate a contribution of ETB-R in basal nitric oxide (NO) release in EA and suggest dilatory action of ETA-R in EA. Conclusions. ETA-R mediates vasoconstriction in AA and contributes to vasoconstriction in EA in this mouse model. ETB-R has no effect in AA but mediates basal NO release and constriction in EA. The stronger effect of ET-1 on AA supports observations of decreased glomerular filtration rate to ET-1 and indicates a potential contribution of ET-1 to the pathogenesis of kidney diseases.}, language = {en} } @article{FoellerMahmudQadrietal.2010, author = {Foeller, Michael and Mahmud, Hasan and Qadri, Syed M. and Gu, Shuchen and Braun, Manuel and Bobbala, Diwakar and Hocher, Berthold and Lang, Florian}, title = {Endothelin B receptor stimulation inhibits suicidal erythrocyte death}, issn = {0892-6638}, doi = {10.1096/Fj.10-159483}, year = {2010}, abstract = {Endothelins (ETs), potent endothelium-derived mediators, stimulate formation of nitric oxide, which, in turn, protects against suicidal erythrocyte death or eryptosis, characterized by phosphatidylserine exposure at the erythrocyte surface and triggered by increase in cytosolic Ca2+ ([Ca2+](i)). The present study explored whether the ET1- receptor ETB influences suicidal erythrocyte death. To this end, [Ca2+](i) (Fluo3-fluorescence) and phosphatidylserine exposure (annexin V-binding) were determined utilizing FACS analysis. Energy depletion increased [Ca2+]i and phosphatidylserine-exposure, effects significantly blunted by ET1 (IC50 approximate to 100 nM) and the ETB receptor- agonist sarafotoxin 6c (IC50 approximate to 10 nM) but not by ET2 and ET3. ET1 and sarafotoxin significantly delayed the kinetics of suicidal erythrocyte death following energy depletion. ETB stimulation did not blunt the effect of Ca2+- ionophore ionomycin (1 mu M) on phosphatidylserine exposure. The in vivo significance was tested using rescued ETB- knockout (etb(-/-)) and wild-type (etb(+/+)) mice. The number of phosphatidylserine-exposing erythrocytes, of reticulocytes and spleen size were significantly larger in etb(-/-) mice than in etb(+/+)-mice. The etb(-/-) erythrocytes were more susceptible to the eryptotic effect of oxidative stress and more rapidly cleared from circulating blood than etb(+/+) erythrocytes. Finally, the spleens from etb(-/-) mice were enlarged and contained markedly more phosphatidylserine- exposing erythrocytes than spleens from etb(+/+) mice. The observations disclose a novel function of ET1, i. e., protection from suicidal erythrocyte death.}, language = {en} } @article{VickersCheethamBirminghametal.2012, author = {Vickers, Steven P. and Cheetham, Sharon C. and Birmingham, Gareth D. and Rowley, Helen L. and Headland, Katie R. and Dickinson, Keith and Grempler, Rolf and Hocher, Berthold and Mark, Michael and Klein, Thomas}, title = {Effects of the DPP-4 Inhibitor, Linagliptin, in Diet-Induced obese rats a comparison in Naive and Exenatide-Treated Animals}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {7-8}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2011.110919}, pages = {787 -- 799}, year = {2012}, abstract = {Background: To assess the chronic effect of the DPP-4 inhibitor, linagliptin, alone, in combination with exenatide, and during exenatide withdrawal, in diet-induced obese (DIO) rats. Methods: Female Wistar rats were exposed to a cafeteria diet to induce obesity. Animals were then dosed with vehicle or linagliptin (3 mg/kg PO) orally once-daily for a 28 day period. In a subsequent study, rats received exenatide (either 3 or 30 mu g/kg/day) or vehicle by osmotic mini-pump for 28 days. In addition, groups of animals were dosed orally with linagliptin either alone or in combination with a 3 mu g/kg/day exenatide dose for the study duration. In a final study, rats were administered exenatide (30 mu g/kg/day) or vehicle by osmotic mini-pump for eleven days. Subsequently, exenatide-treated animals were transferred to vehicle or continued exenatide infusion for a further ten days. Animals transferred from exenatide to vehicle were also dosed orally with either vehicle or linagliptin. In all studies, body weight, food and water intake were recorded daily and relevant plasma parameters and carcass composition were determined. Results: In contrast to exenatide, linagliptin did not significantly reduce body weight or carcass fat in DIO rats versus controls. Linagliptin augmented the effect of exenatide to reduce body fat when given in combination but did not affect the body weight response. In rats withdrawn from exenatide, weight regain was observed such that body weight was not significantly different to controls. Linagliptin reduced weight regain after withdrawal of exenatide such that a significant difference from controls was evident. Conclusions: These data demonstrate that linagliptin does not significantly alter body weight in either untreated or exenatide-treated DIO rats, although it delays weight gain after exenatide withdrawal. This finding may suggest the utility of DPP-4 inhibitors in reducing body weight during periods of weight gain.}, language = {en} } @article{ChaykovskaAltervonWebskyetal.2013, author = {Chaykovska, Lyubov and Alter, Markus L. and von Websky, Karoline and Hohmann, Margarete and Tsuprykov, Oleg and Reichetzeder, Christoph and Kutil, Barbara and Kraft, Robin and Klein, Thomas and Hocher, Berthold}, title = {Effects of telmisartan and linagliptin when used in combination on blood pressure and oxidative stress in rats with 2-kidney-1-clip hypertension}, series = {Journal of hypertension}, volume = {31}, journal = {Journal of hypertension}, number = {11}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {0263-6352}, doi = {10.1097/HJH.0b013e3283649b4d}, pages = {2290 -- 2299}, year = {2013}, abstract = {Objective:To investigate the effects of linagliptin alone and in combination with the angiotensin II receptor blocker (ARB), telmisartan on blood pressure (BP), kidney function, heart morphology and oxidative stress in rats with renovascular hypertension.Methods:Fifty-seven male Wistar rats underwent unilateral surgical stenosis of the renal artery [2-kidney-1-clip (2k1c) method]. Animals were randomly divided into four treatment groups (n=14-18 per group) receiving: telmisartan (10mg/kg per day in drinking water), linagliptin (89ppm in chow), combination (linagliptin 89ppm+telmisartan 10mg/kg per day) or placebo. An additional group of 12 rats underwent sham surgery. BP was measured one week after surgery. Hypertensive animals entered a 16-week dosing period. BP was measured 2, 4, 8, 12 and 16 weeks after the initiation of treatment. Blood and urine were tested for assessment of kidney function and oxidative stress 6, 10, 14 and 18 weeks after surgery. Blood and urine sampling and organ harvesting were finally performed.Results:Renal stenosis caused an increase in meanSD systolic BP as compared with the sham group (157.7 +/- 29.3 vs. 106.2 +/- 20.5mmHg, respectively; P<0.001). Telmisartan alone and in combination with linagliptin, normalized SBP (111.1 +/- 24.3mmHg and 100.4 +/- 13.9mmHg, respectively; P<0.001 vs. placebo). Telmisartan alone and in combination with linagliptin significantly prevented cardiac hypertrophy, measured by heart weight and myocyte diameter. Renal function measured by cystatin C was not affected by 2k1c surgery. Telmisartan significantly increased plasma concentration of cystatin C. 2k1c surgery initiated fibrosis in both kidneys. Telmisartan promoted further fibrotic changes in the clipped kidney, as measured by protein expression of Col1a1 and histology for interstitial fibrosis and glomerulosclerosis. In non-clipped kidneys, telmisartan demonstrated antifibrotic properties, reducing Col1a1 protein expression. Plasma levels of oxidized low-density lipoprotein were higher in the placebo-treated 2k1c rats as compared to sham-operated animals. The increase was abolished by linagliptin alone (P=0.03 vs. placebo) and in combination with telmisartan (P=0.02 vs. placebo). Combination therapy also significantly reduced plasma concentration of carbonyl proteins (P=0.04 vs. placebo).Conclusion:Inhibition of type 4 dipeptidyl peptidase with linagliptin did not counter BP-lowering effects of ARB in 2k1c rats. Linagliptin reduced lipid and protein oxidation in 2k1c rats, and this effect was BP-independent.}, language = {en} } @article{OttAltervonWebskyetal.2012, author = {Ott, Ina M. and Alter, Markus L. and von Websky, Karoline and Kretschmer, Axel and Tsuprykov, Oleg and Sharkovska, Yuliya and Krause-Relle, Katharina and Raila, Jens and Henze, Andrea and Stasch, Johannes-Peter and Hocher, Berthold}, title = {Effects of Stimulation of Soluble Guanylate Cyclase on Diabetic Nephropathy in Diabetic eNOS Knockout Mice on Top of Angiotensin II Receptor Blockade}, series = {PLOS ONE}, volume = {7}, journal = {PLOS ONE}, number = {8}, publisher = {PUBLIC LIBRARY SCIENCE}, address = {SAN FRANCISCO}, issn = {1932-6203}, doi = {10.1371/journal.pone.0042623}, pages = {9}, year = {2012}, abstract = {The prevalence of diabetes mellitus and its complications, such as diabetic nephropathy (DN), is rising worldwide and prevention and treatment are therefore becoming increasingly important. Therapy of DN is particularly important for patients who do not adequately respond to angiotensin receptor blocker (ARB) treatment. Novel approaches include the stimulation of soluble guanylate cyclase (sGC) as it is reported to have beneficial effects on cardiac and renal damage. We aimed to investigate the effects of the sGC stimulator riociguat and ARB telmisartan on kidney function and structure in a hypertensive model of diabetic nephropathy. Seventy-six diabetic male eNOS knockout C57BL/6J mice were randomly divided after having received streptozotocin: telmisartan (1 mg/kg/d), riociguat (3 mg/kg/d), riociguat+telmisartan (3+1 mg/kg/d), and vehicle. Fourteen mice were used as non-diabetic controls. Treatment duration was 11 weeks. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan insignificantly reduced blood pressure by 5.9 mmHg compared with diabetic controls (111.2 +/- 2.3 mmHg vs. 117.1 +/- 2.2 mmHg; p = 0.071). Treatment with riociguat both alone and in combination with telmisartan led to a significant reduction of blood pressure towards diabetic vehicle (105.2 +/- 2.5 mmHg and 105.0 +/- 3.2 mmHg, respectively, vs. 117.1 +/- 2.2 mmHg). Combined treatment also significantly decreased albuminuria compared with diabetic controls (47.3 +/- 9.6 mu g/24 h vs. 170.8 +/- 34.2 mu g/24 h; p = 0.002) reaching levels similar to those of non-diabetic controls (34.4 +/- 10.6 mu g/24 h), whereas the reduction by single treatment with either telmisartan (97.8 +/- 26.4 mu g/24 h) or riociguat (97.1 +/- 15.7 mu g/24 h) was not statistically significant. The combination treatment led to a significant (p < 0.01) decrease of tissue immunoreactivity of malondialdehyde, as consequence of reduced oxidative stress. In conclusion, stimulation of sGC significantly reduced urinary albumin excretion in diabetic eNOS knockout mice treated already with ARB. Thus, this new drug class on top of standard ARBs administration may offer a new therapeutic approach for patients resistant to ARB treatment.}, language = {en} } @article{ChenWangWangetal.2014, author = {Chen, Yao and Wang, Guang and Wang, Xiao-yu and Ma, Zheng-lai and Chen, You-peng and Chuai, Manli and von Websky, Karoline and Hocher, Berthold and Yang, Xuesong}, title = {Effects of high salt-exposure on the development of retina and lens in 5.5-Day Chick Embryo}, series = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, volume = {34}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, number = {3}, publisher = {Karger}, address = {Basel}, issn = {1015-8987}, doi = {10.1159/000363044}, pages = {804 -- 817}, year = {2014}, abstract = {Background/Aims: Excess maternal salt intake during pregnancy may alter fetal development. However; our knowledge on how an increased salt intake during pregnancy influences fetal eye development is limited. In this study, we investigated the effects of high salt treatment on the developing eyes in chick embryos, especially focusing on the development of the retina and the lens. Methods: 5.5 day chick embryos were exposed to 280mosm/l (n=17), or 300mosm/l (n=16) NaCl. The treated embryos were then incubated for 96 hours before they were fixed with 4\% paraformaldehyde for H\&E staining, whole mount embryo immunostaining and TUNEL staining. BrdU and PH3 incorporation experiments were performed on the chick embryos after high salt treatment. RT-PCR analyses were conducted from chick retina tissues. Results: We demonstrated that high-salt treatment altered the size of eyes in chick embryos, induced malformation of the eyes and impaired the development of the lens and the retina. We found an impaired expression of Paired box 6 (PAX6) and neuronal cells in the developing retina as revealed by neurofilament immunofluorescent staining. There was a reduction in the number of BrdU-positive cells and PH3-positive cells in the retina, indicating an impaired cell proliferation with high salt treatment. High salt treatment also resulted in an increased number of TUNEL-positive cells in the retina, indicating a higher amount of cell death. RT-PCR data displayed that the expression of the pro-apoptotic molecule nerve growth factor (NGF) in chick retina was increased and CyclinD1 was reduced with high-salt treatment. The size of the lens was reduced and Pax6 expression in the lens was significantly inhibited. High salt treatment was detrimental to the migration of neural crest cells. Conclusion: Taken together; our study demonstrated that high salt exposure of 5.5 day chick embryos led to an impairment of retina and lens development, possibly through interfering with Pax6 expression.}, language = {en} } @article{ChaykovskavonWebskyRahnenfuehreretal.2011, author = {Chaykovska, Lyubov and von Websky, Karoline and Rahnenf{\"u}hrer, Jan and Alter, Markus L. and Heiden, Susi and Fuchs, Holger and Runge, Frank and Klein, Thomas and Hocher, Berthold}, title = {Effects of DPP-4 Inhibitors on the Heart in a Rat Model of Uremic Cardiomyopathy}, series = {PLoS one}, volume = {6}, journal = {PLoS one}, number = {11}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0027861}, pages = {9}, year = {2011}, abstract = {Background: Uremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD) patients. Glucagon-like peptide-1 (GLP-1) may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4). Methodology/Principal Findings: In a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin) or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant change in blood level AUC(0-infinity) in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-infinity) values; 41\% and 28\% (p=0.0001 and p=0.0324), respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 mu mol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h) in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h) (p=0.01). The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin. Conclusions/Significance: DPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP). Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment.}, language = {en} } @article{FegerFajolLebedevaetal.2013, author = {Feger, Martina and Fajol, Abul and Lebedeva, Aleksandra and Meissner, Adrian and Michael, Diana and V{\"o}lkl, Jakob and Alesutan, Ioana and Schleicher, Erwin and Reichetzeder, Christoph and Hocher, Berthold and Qadri, Syed M. and Lang, Florian}, title = {Effect of Carbon Monoxide Donor CORM-2 on Vitamin D-3 Metabolism}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, volume = {37}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, number = {4-5}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000355730}, pages = {496 -- 505}, year = {2013}, abstract = {Background/Aims: Carbon monoxide (CO) interferes with cytochrome-dependent cellular functions and acts as gaseous transmitter. CO is released from CO-releasing molecules (CORM) including tricarbonyl-dichlororuthenium (II) dimer (CORM-2), molecules considered for the treatment of several disorders including vascular dysfunction, inflammation, tissue ischemia and organ rejection. Cytochrome P450-sensitive function include formation of 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) by renal 25-hydroxyvitamin D-3 1-alpha-hydroxylase (Cyp27b1). The enzyme is regulated by PTH, FGF23 and klotho. 1,25(OH)(2)D-3 regulates Ca2+ and phosphate transport as well as klotho expression. The present study explored, whether CORM-2 influences 1,25(OH)(2)D-3 formation and klotho expression. Methods: Mice were treated with intravenous CORM-2 (20 mg/kg body weight). Plasma 1,25(OH)(2)D-3 and FGF23 concentrations were determined by ELISA, phosphate, calcium and creatinine concentrations by colorimetric methods, transcript levels by quantitative RT-PCR and protein expression by western blotting. Fgf23 mRNA transcript levels were further determined in rat osteosarcoma UMR106 cells without or with prior treatment for 24 hours with 20 mu M CORM-2. Results: CORM-2 injection within 24 hours significantly increased FGF23 plasma levels and decreased 1,25(OH)(2)D-3 plasma levels, renal Cyp27b1 gene expression as well as renal klotho protein abundance and transcript levels. Moreover, treatment of UMR106 cells with CORM-2 significantly increased Fgf23 transcript levels. Conclusion: CO-releasing molecule CORM-2 enhances FGF23 expression and release and decreases klotho expression and 1,25(OH)(2)D-3 synthesis.}, language = {en} } @article{AlterKretschmerVonWebskyetal.2012, author = {Alter, Markus L. and Kretschmer, Axel and Von Websky, Karoline and Tsuprykov, Oleg and Reichetzeder, Christoph and Simon, Alexandra and Stasch, Johannes-Peter and Hocher, Berthold}, title = {Early urinary and plasma biomarkers for experimental diabetic Nephropathy}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {7-8}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2011.111010}, pages = {659 -- 671}, year = {2012}, abstract = {Background: As the prevalence of diabetes rises, its complications such as diabetic nephropathy affect an increaseing number of patients. Consequently, the need for biomarkers in rodent models which reflect the stage and course of diabetic nephropathy is high. This article focuses on Heart-type fatty acid binding protein (H-FABP), osteopontin (OPN), nephrin, and Neutrophil gelatinase-associated lipocalin (NGAL) in urine, and kidney injury molecule (KIM)-1, clusterin, and tissue inhibitior of metalloproteinases (TIMP) 1 in plasma in uni-nephrectomized rats with streptocotozin-induced type 1 diabetes mellitus, a common animal model to explore renal impairment in the setting of diabetes mellitus. Methods: 23 male Wistar rats were uni-nephrectomized and subsequently divided into two study groups. The diabetic group received streptozotocin (STZ) via tail-vein injection, the non-diabetic group received citrate buffer without STZ. Subsequently, blood glucose, body weight, and blood pressure were checked regularly. After 18 weeks, animals were placed in metabolic cages, blood and urine obtained and subsequently organs were harvested after sacrifice. Results: Blood glucose levels were highly increased in diabetic animals throughout the experiment, whereas systolic blood pressure did not differ between the study groups. At study end, classical biomarkers such as urinary albumin and protein and plasma cystatin c were only slightly but not significantly different between groups indicating a very early disease state. In contrast, urinary excretion of H-FABP, OPN, nephrin, and NGAL were highly increased in diabetic animals with a highly significant p-value (p<0.01 each) compared to non-diabetic animals. In plasma, differences were found for calbindin, KIM-1, clusterin, TIMP-1, and OPN. These findings were confirmed by means of the area under the receiver operating characteristic curve (ROC-AUC) analysis. Conclusions: In summary, our study revealed elevated levels of new plasma and urinary biomarkers (urinary osteopontin, urinary nephrin, urinary NGAL, urinary H-FABP, plasma KIM-1, plasma TIMP-1) in uni-nephrectomized diabetic rats, an established rat model of diabetic nephropathy. These biomarkers appeared even before the classical biomarkers of diabetic nephropathy such as albuminuria and urinary protein excretion. The new biomarkers might offer advantage to urinary albumin and plasma cystatin c with respect to early detection.}, language = {en} } @article{HocherHeidenvonWebskyetal.2011, author = {Hocher, Berthold and Heiden, S. and von Websky, Karoline and Rahnenf{\"u}hrer, J{\"o}rg and Kalk, Philipp and Pfab, T.}, title = {Dual endothelin-converting enzyme/neutral endopeptidase blockade in rats with D-galactosamine-induced liver failure}, series = {European journal of medical research : official organ "Deutsche AIDS-Gesellschaft"}, volume = {16}, journal = {European journal of medical research : official organ "Deutsche AIDS-Gesellschaft"}, number = {6}, publisher = {Med. Scientific Publ. Holzapfel}, address = {M{\"u}nchen}, issn = {0949-2321}, pages = {275 -- 279}, year = {2011}, abstract = {Secondary activation of the endothelin system is thought to be involved in toxic liver injury. This study tested the hypothesis that dual endothelin-converting enzyme / neutral endopeptidase blockade might: be able to attenuate acute toxic liver injury. Male Sprague-Dawley rats were implanted with subcutaneous minipumps to deliver the novel compound SLV338 (10 mg/kg*d) or vehicle. Four days later they received two intraperitoneal injections of D-galactosamine (1.3 g/kg each) or vehicle at an interval of 12 hours. The animals were sacrificed 48 hours after the first injection. Injection of D-galactosamine resulted in very severe liver injury, reflected by strongly elevated plasma liver enzymes, hepatic necrosis and inflammation, and a mortality rate of 42.9 \%. SLV338 treatment did not show any significant effect on the extent of acute liver injury as judged from plasma parameters, hepatic histology and mortality. Plasma measurements of SLV338 confirmed adequate drug delivery. Plasma concentrations of big endothelin-1 and endothelin-1 were significantly elevated in animals with liver injury (5-fold and 62-fold, respectively). Plasma endothelin-1 was significantly correlated with several markers of liver injury. SLV338 completely prevented the rise of plasma big endothelin-1 (p<0.05) and markedly attenuated the rise of endothelin-1 (p = 0.055). In conclusion, dual endothelin-converting enzyme / neutral endopeptidase blockade by SLV338 did not significantly attenuate D-galactosamine-induced acute liver injury, although it largely prevented the activation of the endothelin system. An evaluation of SLV338 in a less severe model of liver injury would be of interest, since very severe intoxication might not be relevantly amenable to pharmacological interventions.}, language = {en} } @article{AlterOttvonWebskyetal.2012, author = {Alter, Markus L. and Ott, Ina M. and von Websky, Karoline and Tsuprykov, Oleg and Sharkovska, Yuliya and Krause-Relle, Katharina and Raila, Jens and Henze, Andrea and Klein, Thomas and Hocher, Berthold}, title = {DPP-4 Inhibition on top of angiotensin receptor blockade offers a new therapeutic approach for diabetic nephropathy}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, volume = {36}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, number = {1}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000341487}, pages = {119 -- 130}, year = {2012}, abstract = {Background: The need for an improved treatment for diabetic nephropathy is greatest in patients who do not adequately respond to angiotensin II receptor blockers (ARBs). This study investigated the effect of the novel dipeptidyl peptidase-4 inhibitor linagliptin alone and in combination with the ARB telmisartan on the progression of diabetic nephropathy in diabetic endothelial nitric oxide synthase (eNOS) knockout mice. Methods: Sixty male eNOS knockout C57BL/6J mice were divided into four groups after receiving intraperitoneal high-dose streptozotocin: telmisartan (1 mg/kg), linagliptin (3 mg/kg), linagliptin + telmisartan (3 mg/kg + 1 mg/kg) and vehicle. Fourteen mice were used as non-diabetic controls. Results: After 12 weeks, urine and blood were obtained and blood pressure measured. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan alone reduced systolic blood pressure by 5.9 mmHg versus diabetic controls (111.2 +/- 2.3 mmHg vs 117.1 +/- 2.2 mmHg; mean +/- SEM; P = 0.071). Combined treatment significantly reduced albuminuria compared with diabetic controls (71.7 +/- 15.3 mu g/24 h vs 170.8 +/- 34.2 mu g/24 h; P = 0.017), whereas the effects of single treatment with either telmisartan (97.8 +/- 26.4 mu g/24 h) or linagliptin (120.8 +/- 37.7 mu g/24 h) were not statistically significant. DPP-4 inhibition, alone and in combination, led to significantly lower plasma osteopontin levels compared with telmisartan alone. Histological analysis revealed reduced glomerulosclerosis after Linagliptin alone and in combination with telmisartan in comparison to non treated diabetic animals (p < 0.01 and p < 0.05). Kidney malonaldehyde immune-reactivity, a marker of oxidative stress, was significantly lower in animals treated with linagliptin. Conclusions: DPP-4 inhibition on top of ARB treatment significantly reduced urinary albumin excretion and oxidative stress in diabetic eNOS knockout mice. Linagliptin on top of an angiotensin II receptor blocker may offer a new therapeutic approach for patients with diabetic nephropathy.}, language = {en} } @article{TaoSuXuetal.2018, author = {Tao, Ting and Su, Qiongli and Xu, Simeng and Deng, Jun and Zhou, Sichun and Zhuang, Yu and Huang, Yanjun and He, Caimei and He, Shanping and Peng, Mei and Hocher, Berthold and Yang, Xiaoping}, title = {Down-regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP-1c axis}, series = {Journal of cellular physiology}, volume = {234}, journal = {Journal of cellular physiology}, number = {3}, publisher = {Wiley}, address = {Hoboken}, issn = {0021-9541}, doi = {10.1002/jcp.27129}, pages = {3088 -- 3104}, year = {2018}, abstract = {Fatty acid synthase (FASN) catalyzing the terminal steps in the de novo biogenesis of fatty acids is correlated with low survival and high disease recurrence in patients with bladder cancer. Pyruvate kinase M2 (PKM2) regulates the final step of glycolysis levels and provides a growth advantage to tumors. However, it is unclear whether the change of PKM2 has an effect on FASN and what is the mechanisms underlying. Here we describe a novel function of PKM2 in control of lipid metabolism by mediating transcriptional activation of FASN, showing the reduced expression of sterol regulatory element binding protein 1c (SREBP-1c). We first discovered that PKM2 physically interacts with the SREBP-1c using biochemical approaches, and downregulation of PKM2 reduced the expression of SREBP-1c by inactivating the AKT/mTOR signaling pathway, which in turn directly suppressed the transcription of major lipogenic genes FASN to reduce tumor growths. Furthermore, either PKM2 inhibitor-Shikonin or FASN inhibitor-TVB-3166 alone induced a strong antiproliferative and anticolony forming effect in bladder cancer cell line. The combination of both inhibitors exhibits a super synergistic effect on blocking the bladder cancer cells growth. It provides a new target and scientific basis for the treatment of bladder cancer.}, language = {en} } @article{PutraReichetzederMeixneretal.2017, author = {Putra, Sulistyo E. Dwi and Reichetzeder, Christoph and Meixner, Martin and Liere, Karsten and Slowinski, Torsten and Hocher, Berthold}, title = {DNA methylation of the glucocorticoid receptor gene promoter in the placenta is associated with blood pressure regulation in human pregnancy}, series = {Journal of hypertension}, volume = {35}, journal = {Journal of hypertension}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {0263-6352}, doi = {10.1097/HJH.0000000000001450}, pages = {2276 -- 2286}, year = {2017}, abstract = {Background: Blood pressure (BP) regulation during pregnancy is influenced by hormones of placental origin. It was shown that the glucocorticoid system is altered in hypertensive pregnancy disorders such as preeclampsia. Epigenetic mechanism might influence the activity of genes involved in placental hormone/hormone receptor synthesis/action during pregnancy. Method: In the current study, we analyzed the association of 50-C-phosphate-G-30 (CpG) site methylation of different glucocorticoid receptor gene (NR3C1) promoter regions with BP during pregnancy. The study was performed as a nested case-control study (n = 80) out of 1045 mother/ child pairs from the Berlin Birth Cohort. Placental DNA was extracted and bisulfite converted. Nested PCR products from six NR3C1 proximal promoter regions [glucocorticoid receptor gene promotor region B (GR-1B), C (GR-1C), D (GR-1D), E (GR-1E), F (GR-1F), and H (GR-1H)] were analyzed by next generation sequencing. Results: NR3C1 promoter regions GR-1D and GR-1E had a much higher degree of DNA methylation as compared to GR-1B, GR-1F or GR-1H when analyzing the entire study population. Comparison of placental NR3C1 CpG site methylation among hypotensive, normotensive and hypertensive mothers revealed several differently methylated CpG sites in the GR-1F promoter region only. Both hypertension and hypotension were associated with increased DNA methylation of GR-1F CpG sites. These associations were independent of confounding factors, such as family history of hypertension, smoking status before pregnancy and prepregnancy BMI. Assessment of placental glucocorticoid receptor expression by western blot showed that observed DNA methylation differences were not associated with altered levels of placental glucocorticoid receptor expression. However, correlation matrices of all NR3C1 proximal promoter regions demonstrated different correlation patterns of intraregional and interregional DNA methylation in the three BP groups, putatively indicating altered transcriptional control of glucocorticoid receptor isoforms. Conclusion: Our study provides evidence of an independent association between placental NR3C1 proximal promoter methylation and maternal BP. Furthermore, we observed different patterns of NR3C1 promoter methylation in normotensive, hypertensive and hypotensive pregnancy.}, language = {en} } @article{ZirafiKimStaendkeretal.2015, author = {Zirafi, Onofrio and Kim, Kyeong-Ae and St{\"a}ndker, Ludger and Mohr, Katharina B. and Sauter, Daniel and Heigele, Anke and Kluge, Silvia F. and Wiercinska, Eliza and Chudziak, Doreen and Richter, Rudolf and M{\"o}pps, Barbara and Gierschik, Peter and Vas, Virag and Geiger, Hartmut and Lamla, Markus and Weil, Tanja and Burster, Timo and Zgraja, Andreas and Daubeuf, Francois and Frossard, Nelly and Hachet-Haas, Muriel and Heunisch, Fabian and Reichetzeder, Christoph and Galzi, Jean-Luc and Perez-Castells, Javier and Canales-Mayordomo, Angeles and Jimenez-Barbero, Jesus and Gimenez-Gallego, Guillermo and Schneider, Marion and Shorter, James and Telenti, Amalio and Hocher, Berthold and Forssmann, Wolf-Georg and Bonig, Halvard and Kirchhoff, Frank and M{\"u}nch, Jan}, title = {Discovery and Characterization of an Endogenous CXCR4 Antagonist}, series = {Cell reports}, volume = {11}, journal = {Cell reports}, number = {5}, publisher = {Cell Press}, address = {Cambridge}, issn = {2211-1247}, doi = {10.1016/j.celrep.2015.03.061}, pages = {737 -- 747}, year = {2015}, abstract = {CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.}, language = {en} } @article{GroopCooperPerkovicetal.2015, author = {Groop, Per-Henrik and Cooper, Mark E. and Perkovic, Vlado and Sharma, Kumar and Schernthaner, Guntram and Haneda, Masakazu and Hocher, Berthold and Gordat, Maud and Cescutti, Jessica and Woerle, Hans-Juergen and von Eynatten, Maximilian}, title = {Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: Rationale and design of the MARLINA-T2D trial}, series = {Diabetes \& vascular disease research : official journal of the International Society of Diabetes and Vascular Disease}, volume = {12}, journal = {Diabetes \& vascular disease research : official journal of the International Society of Diabetes and Vascular Disease}, number = {6}, publisher = {Sage Publ.}, address = {London}, issn = {1479-1641}, doi = {10.1177/1479164115579002}, pages = {455 -- 462}, year = {2015}, abstract = {Efficacy, Safety \& Modification of Albuminuria in Type 2 Diabetes Subjects with Renal Disease with LINAgliptin (MARLINA-T2D), a multicentre, multinational, randomized, double-blind, placebo-controlled, parallel-group, phase 3b clinical trial, aims to further define the potential renal effects of dipeptidyl peptidase-4 inhibition beyond glycaemic control. A total of 350 eligible individuals with inadequately controlled type 2 diabetes and evidence of renal disease are planned to be randomized in a 1:1 ratio to receive either linagliptin 5mg or placebo in addition to their stable glucose-lowering background therapy for 24weeks. Two predefined main endpoints will be tested in a hierarchical manner: (1) change from baseline in glycated haemoglobin and (2) time-weighted average of percentage change from baseline in urinary albumin-to-creatinine ratio. Both endpoints are sufficiently powered to test for superiority versus placebo after 24weeks with =0.05. MARLINA-T2D is the first of its class to prospectively explore both the glucose- and albuminuria-lowering potential of a dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes and evidence of renal disease.}, language = {en} } @article{ChaykovskaZientaraReseretal.2014, author = {Chaykovska, Lyubov and Zientara, Alicja and Reser, Diana and Weise, Alexander and Reichert, Wolfgang and Hocher, Berthold}, title = {Development and validation of a macroarray system - MutaCHIP (R) ARTERO - for the detection of genetic variants involved in the pathogenesis of atherosclerosis}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {60}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {5}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2014.140104}, pages = {873 -- 878}, year = {2014}, abstract = {Background: Cardiovascular diseases are the leading cause of death in developed countries. The underlying mechanism is often atherosclerotic remodeling of blood vessels in organs such as heart, kidney, brain, and large arteries in case of peripheral arterial disease. Beside environmental and behavioral factors such as smoking or lack of physical activity, genetic variants in genes involved in lipid metabolism, blood pressure regulation, oxidative stress, and coagulation play a prominent role in the pathogenesis of atherosclerosis. Methods: Thus, we developed and validated for clinical use and research a macroarray system for the simultaneous detection of key genetic variants in genes involved in lipid metabolism, blood pressure regulation, oxidative stress, and coagulation. Results: When compared with standard PCR technologies to determine all these genetic variants in parallel, the macroarray system (MutaCHIP (R) ARTERO) was as accurate but faster, cheaper, and easier to handle compared to classical real time PCR based technologies. Conclusions: MutaCHIP (R) ARTERO is a gene chip for diagnostics of a complex genetic panel involved in the pathogenesis of atherosclerosis. This method is as sensitive and precise as real time PCR and is able to replicate real time PCR data previously validated in evaluation studies.}, language = {en} } @article{PutraTsuprykovVonWebskyetal.2014, author = {Putra, Sulistyo Emantoko Dwi and Tsuprykov, Oleg and Von Websky, Karoline and Ritter, Teresa and Reichetzeder, Christoph and Hocher, Berthold}, title = {Dealing with large sample sizes: comparison of a new one spot dot blot method to western blot}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {60}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {11}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2014.140317}, pages = {1871 -- 1877}, year = {2014}, abstract = {Background: Western blot is the gold standard method to determine individual protein expression levels. However, western blot is technically difficult to perform in large sample sizes because it is a time consuming and labor intensive process. Dot blot is often used instead when dealing with large sample sizes, but the main disadvantage of the existing dot blot techniques, is the absence of signal normalization to a housekeeping protein. Methods: In this study we established a one dot two development signals (ODTDS) dot blot method employing two different signal development systems. The first signal from the protein of interest was detected by horseradish peroxidase (HRP). The second signal, detecting the housekeeping protein, was obtained by using alkaline phosphatase (AP). Results: Inter-assay results variations within ODTDS dot blot and western blot and intra-assay variations between both methods were low (1.04 - 5.71\%) as assessed by coefficient of variation. Conclusions: ODTDS dot blot technique can be used instead of western blot when dealing with large sample sizes without a reduction in results accuracy.}, language = {en} } @article{LuReichetzederPrehnetal.2018, author = {Lu, Yong-Ping and Reichetzeder, Christoph and Prehn, Cornelia and Yin, Liang-Hong and Yun, Chen and Zeng, Shufei and Chu, Chang and Adamski, Jerzy and Hocher, Berthold}, title = {Cord blood Lysophosphatidylcholine 16:1 is positively associated with birth weight}, series = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, volume = {45}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, number = {2}, publisher = {Karger}, address = {Basel}, issn = {1015-8987}, doi = {10.1159/000487118}, pages = {614 -- 624}, year = {2018}, abstract = {Background/Aims: Impaired birth outcomes, like low birth weight, have consistently been associated with increased disease susceptibility to hypertension in later life. Alterations in the maternal or fetal metabolism might impact on fetal growth and influence birth outcomes. Discerning associations between the maternal and fetal metabolome and surrogate parameters of fetal growth could give new insight into the complex relationship between intrauterine conditions, birth outcomes, and later life disease susceptibility. Methods: Using flow injection tandem mass spectrometry, targeted metabolomics was performed in serum samples obtained from 226 mother/child pairs at delivery. Associations between neonatal birth weight and concentrations of 163 maternal and fetal metabolites were analyzed. Results: After FDR adjustment using the Benjamini-Hochberg procedure lysophosphatidylcholines (LPC) 14:0, 16:1, and 18:1 were strongly positively correlated with birth weight. In a stepwise linear regression model corrected for established confounding factors of birth weight, LPC 16: 1 showed the strongest independent association with birth weight (CI: 93.63 - 168.94; P = 6.94x10(-11)). The association with birth weight was stronger than classical confounding factors such as offspring sex (CI: - 258.81- -61.32; P = 0.002) and maternal smoking during pregnancy (CI: -298.74 - -29.51; P = 0.017). Conclusions: After correction for multiple testing and adjustment for potential confounders, LPC 16:1 showed a very strong and independent association with birth weight. The underlying molecular mechanisms linking fetal LPCs with birth weight need to be addressed in future studies. (c) 2018 The Author(s) Published by S. Karger AG, Basel}, language = {en} } @article{IkramFornageSmithetal.2012, author = {Ikram, M. Arfan and Fornage, Myriam and Smith, Albert V. and Seshadri, Sudha and Schmidt, Reinhold and Debette, Stephanie and Vrooman, Henri A. and Sigurdsson, Sigurdur and Ropele, Stefan and Taal, H. Rob and Mook-Kanamori, Dennis O. and Coker, Laura H. and Longstreth, W. T. and Niessen, Wiro J. and DeStefano, Anita L. and Beiser, Alexa and Zijdenbos, Alex P. and Struchalin, Maksim and Jack, Clifford R. and Rivadeneira, Fernando and Uitterlinden, Andre G. and Knopman, David S. and Hartikainen, Anna-Liisa and Pennell, Craig E. and Thiering, Elisabeth and Steegers, Eric A. P. and Hakonarson, Hakon and Heinrich, Joachim and Palmer, Lyle J. and Jarvelin, Marjo-Riitta and McCarthy, Mark I. and Grant, Struan F. A. and St Pourcain, Beate and Timpson, Nicholas J. and Smith, George Davey and Sovio, Ulla and Nalls, Mike A. and Au, Rhoda and Hofman, Albert and Gudnason, Haukur and van der Lugt, Aad and Harris, Tamara B. and Meeks, William M. and Vernooij, Meike W. and van Buchem, Mark A. and Catellier, Diane and Jaddoe, Vincent W. V. and Gudnason, Vilmundur and Windham, B. Gwen and Wolf, Philip A. and van Duijn, Cornelia M. and Mosley, Thomas H. and Schmidt, Helena and Launer, Lenore J. and Breteler, Monique M. B. and DeCarli, Charles and Adair, Linda S. and Ang, Wei and Atalay, Mustafa and vanBeijsterveldt, Toos and Bergen, Nienke and Benke, Kelly and Berry, Diane J. and Coin, Lachlan and Davis, Oliver S. P. and Elliott, Paul and Flexeder, Claudia and Frayling, Tim and Gaillard, Romy and Groen-Blokhuis, Maria and Goh, Liang-Kee and Haworth, Claire M. A. and Hadley, Dexter and Hebebrand, Johannes and Hinney, Anke and Hirschhorn, Joel N. and Holloway, John W. and Holst, Claus and Hottenga, Jouke Jan and Horikoshi, Momoko and Huikari, Ville and Hypponen, Elina and Kilpelainen, Tuomas O. and Kirin, Mirna and Kowgier, Matthew and Lakka, Hanna-Maaria and Lange, Leslie A. and Lawlor, Debbie A. and Lehtimaki, Terho and Lewin, Alex and Lindgren, Cecilia and Lindi, Virpi and Maggi, Reedik and Marsh, Julie and Middeldorp, Christel and Millwood, Iona and Murray, Jeffrey C. and Nivard, Michel and Nohr, Ellen Aagaard and Ntalla, Ioanna and Oken, Emily and Panoutsopoulou, Kalliope and Pararajasingham, Jennifer and Rodriguez, Alina and Salem, Rany M. and Sebert, Sylvain and Siitonen, Niina and Strachan, David P. and Teo, Yik-Ying and Valcarcel, Beatriz and Willemsen, Gonneke and Zeggini, Eleftheria and Boomsma, Dorret I. and Cooper, Cyrus and Gillman, Matthew and Hocher, Berthold and Lakka, Timo A. and Mohlke, Karen L. and Dedoussis, George V. and Ong, Ken K. and Pearson, Ewan R. and Price, Thomas S. and Power, Chris and Raitakari, Olli T. and Saw, Seang-Mei and Scherag, Andre and Simell, Olli and Sorensen, Thorkild I. A. and Wilson, James F.}, title = {Common variants at 6q22 and 17q21 are associated with intracranial volume}, series = {Nature genetics}, volume = {44}, journal = {Nature genetics}, number = {5}, publisher = {Nature Publ. Group}, address = {New York}, organization = {Early Growth Genetics EGG Consorti, Cohorts Heart Aging Res Genomic Ep}, issn = {1061-4036}, doi = {10.1038/ng.2245}, pages = {539 -- +}, year = {2012}, abstract = {During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.}, language = {en} } @article{TaalStPourcainThieringetal.2012, author = {Taal, H. Rob and St Pourcain, Beate and Thiering, Elisabeth and Das, Shikta and Mook-Kanamori, Dennis O. and Warrington, Nicole M. and Kaakinen, Marika and Kreiner-Moller, Eskil and Bradfield, Jonathan P. and Freathy, Rachel M. and Geller, Frank and Guxens, Monica and Cousminer, Diana L. and Kerkhof, Marjan and Timpson, Nicholas J. and Ikram, M. Arfan and Beilin, Lawrence J. and Bonnelykke, Klaus and Buxton, Jessica L. and Charoen, Pimphen and Chawes, Bo Lund Krogsgaard and Eriksson, Johan and Evans, David M. and Hofman, Albert and Kemp, John P. and Kim, Cecilia E. and Klopp, Norman and Lahti, Jari and Lye, Stephen J. and McMahon, George and Mentch, Frank D. and Mueller-Nurasyid, Martina and O'Reilly, Paul F. and Prokopenko, Inga and Rivadeneira, Fernando and Steegers, Eric A. P. and Sunyer, Jordi and Tiesler, Carla and Yaghootkar, Hanieh and Breteler, Monique M. B. and Debette, Stephanie and Fornage, Myriam and Gudnason, Vilmundur and Launer, Lenore J. and van der Lugt, Aad and Mosley, Thomas H. and Seshadri, Sudha and Smith, Albert V. and Vernooij, Meike W. and Blakemore, Alexandra I. F. and Chiavacci, Rosetta M. and Feenstra, Bjarke and Fernandez-Banet, Julio and Grant, Struan F. A. and Hartikainen, Anna-Liisa and van der Heijden, Albert J. and Iniguez, Carmen and Lathrop, Mark and McArdle, Wendy L. and Molgaard, Anne and Newnham, John P. and Palmer, Lyle J. and Palotie, Aarno and Pouta, Annneli and Ring, Susan M. and Sovio, Ulla and Standl, Marie and Uitterlinden, Andre G. and Wichmann, H-Erich and Vissing, Nadja Hawwa and DeCarli, Charles and van Duijn, Cornelia M. and McCarthy, Mark I. and Koppelman, Gerard H. and Estivill, Xavier and Hattersley, Andrew T. and Melbye, Mads and Bisgaard, Hans and Pennell, Craig E. and Widen, Elisabeth and Hakonarson, Hakon and Smith, George Davey and Heinrich, Joachim and Jarvelin, Marjo-Riitta and Jaddoe, Vincent W. V. and Adair, Linda S. and Ang, Wei and Atalay, Mustafa and van Beijsterveldt, Toos and Bergen, Nienke and Benke, Kelly and Berry, Diane J. and Bradfield, Jonathan P. and Charoen, Pimphen and Coin, Lachlan and Cousminer, Diana L. and Das, Shikta and Davis, Oliver S. P. and Elliott, Paul and Evans, David M. and Feenstra, Bjarke and Flexeder, Claudia and Frayling, Tim and Freathy, Rachel M. and Gaillard, Romy and Geller, Frank and Groen-Blokhuis, Maria and Goh, Liang-Kee and Guxens, Monica and Haworth, Claire M. A. and Hadley, Dexter and Hebebrand, Johannes and Hinney, Anke and Hirschhorn, Joel N. and Holloway, John W. and Holst, Claus and Hottenga, Jouke Jan and Horikoshi, Momoko and Huikari, Ville and Hypponen, Elina and Iniguez, Carmen and Kaakinen, Marika and Kilpelainen, Tuomas O. and Kirin, Mirna and Kowgier, Matthew and Lakka, Hanna-Maaria and Lange, Leslie A. and Lawlor, Debbie A. and Lehtimaki, Terho and Lewin, Alex and Lindgren, Cecilia and Lindi, Virpi and Maggi, Reedik and Marsh, Julie and Middeldorp, Christel and Millwood, Iona and Mook-Kanamori, Dennis O. and Murray, Jeffrey C. and Nivard, Michel and Nohr, Ellen Aagaard and Ntalla, Ioanna and Oken, Emily and O'Reilly, Paul F. and Palmer, Lyle J. and Panoutsopoulou, Kalliope and Pararajasingham, Jennifer and Prokopenko, Inga and Rodriguez, Alina and Salem, Rany M. and Sebert, Sylvain and Siitonen, Niina and Sovio, Ulla and St Pourcain, Beate and Strachan, David P. and Sunyer, Jordi and Taal, H. Rob and Teo, Yik-Ying and Thiering, Elisabeth and Tiesler, Carla and Uitterlinden, Andre G. and Valcarcel, Beatriz and Warrington, Nicole M. and White, Scott and Willemsen, Gonneke and Yaghootkar, Hanieh and Zeggini, Eleftheria and Boomsma, Dorret I. and Cooper, Cyrus and Estivill, Xavier and Gillman, Matthew and Grant, Struan F. A. and Hakonarson, Hakon and Hattersley, Andrew T. and Heinrich, Joachim and Hocher, Berthold and Jaddoe, Vincent W. V. and Jarvelin, Marjo-Riitta and Lakka, Timo A. and McCarthy, Mark I. and Melbye, Mads and Mohlke, Karen L. and Dedoussis, George V. and Ong, Ken K. and Pearson, Ewan R. and Pennell, Craig E. and Price, Thomas S. and Power, Chris and Raitakari, Olli T. and Saw, Seang-Mei and Scherag, Andre and Simell, Olli and Sorensen, Thorkild I. A. and Timpson, Nicholas J. and Widen, Elisabeth and Wilson, James F. and Ang, Wei and van Beijsterveldt, Toos and Bergen, Nienke and Benke, Kelly and Berry, Diane J. and Bradfield, Jonathan P. and Charoen, Pimphen and Coin, Lachlan and Cousminer, Diana L. and Das, Shikta and Elliott, Paul and Evans, David M. and Frayling, Tim and Freathy, Rachel M. and Gaillard, Romy and Groen-Blokhuis, Maria and Guxens, Monica and Hadley, Dexter and Hottenga, Jouke Jan and Huikari, Ville and Hypponen, Elina and Kaakinen, Marika and Kowgier, Matthew and Lawlor, Debbie A. and Lewin, Alex and Lindgren, Cecilia and Marsh, Julie and Middeldorp, Christel and Millwood, Iona and Mook-Kanamori, Dennis O. and Nivard, Michel and O'Reilly, Paul F. and Palmer, Lyle J. and Prokopenko, Inga and Rodriguez, Alina and Sebert, Sylvain and Sovio, Ulla and St Pourcain, Beate and Standl, Marie and Strachan, David P. and Sunyer, Jordi and Taal, H. Rob and Thiering, Elisabeth and Tiesler, Carla and Uitterlinden, Andre G. and Valcarcel, Beatriz and Warrington, Nicole M. and White, Scott and Willemsen, Gonneke and Yaghootkar, Hanieh and Boomsma, Dorret I. and Estivill, Xavier and Grant, Struan F. A. and Hakonarson, Hakon and Hattersley, Andrew T. and Heinrich, Joachim and Jaddoe, Vincent W. V. and Jarvelin, Marjo-Riitta and McCarthy, Mark I. and Pennell, Craig E. and Power, Chris and Timpson, Nicholas J. and Widen, Elisabeth and Ikram, M. Arfan and Fornage, Myriam and Smith, Albert V. and Seshadri, Sudha and Schmidt, Reinhold and Debette, Stephanie and Vrooman, Henri A. and Sigurdsson, Sigurdur and Ropele, Stefan and Coker, Laura H. and Longstreth, W. T. and Niessen, Wiro J. and DeStefano, Anita L. and Beiser, Alexa and Zijdenbos, Alex P. and Struchalin, Maksim and Jack, Clifford R. and Nalls, Mike A. and Au, Rhoda and Hofman, Albert and Gudnason, Haukur and van der Lugt, Aad and Harris, Tamara B. and Meeks, William M. and Vernooij, Meike W. and van Buchem, Mark A. and Catellier, Diane and Gudnason, Vilmundur and Windham, B. Gwen and Wolf, Philip A. and van Duijn, Cornelia M. and Mosley, Thomas H. and Schmidt, Helena and Launer, Lenore J. and Breteler, Monique M. B. and DeCarli, Charles}, title = {Common variants at 12q15 and 12q24 are associated with infant head circumference}, series = {Nature genetics}, volume = {44}, journal = {Nature genetics}, number = {5}, publisher = {Nature Publ. Group}, address = {New York}, organization = {Cohorts Heart Aging Res Genetic Ep, Early Genetics Lifecourse Epidemio, Early Growth Genetics EGG Consorti}, issn = {1061-4036}, doi = {10.1038/ng.2238}, pages = {532 -- +}, year = {2012}, abstract = {To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.}, language = {en} } @article{PengZhuDongetal.2015, author = {Peng, Tao and Zhu, Ganghua and Dong, Yunpeng and Zeng, Junjie and Li, Wei and Guo, Weiwei and Chen, Yong and Duan, Maoli and Hocher, Berthold and Xie, Dinghua}, title = {BMP4: a possible key factor in differentiation of auditory neuron-like cells from bone-derived mesenchymal stromal cells}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {61}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {9}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2015.150217}, pages = {1171 -- 1178}, year = {2015}, abstract = {Background: Previous studies have shown that BMP4 may play an important part in the development of auditory neurons (ANs), which are degenerated in sensorineural hearing loss. However, whether BMP4 can promote sensory fate specification from mesenchymal stromal cells (MSCs) is unknown so far. Methods: MSCs isolated from Sprague-Dawley (SD) rats were confirmed by expression of MSC markers using flow cytometry and adipogenesis/osteogenesis using differentiation assays. MSCs treated with a complex of neurotrophic factors (BMP4 group and non-BMP4 group) were induced into auditory neuron-like cells, then the differences between the two groups were analyzed in morphological observation, cell growth curve, qRT-PCR, and immunofluorescence. Results: Flow cytometric analysis showed that the isolated cells expressed typical MSC surface markers. After adipogenic and osteogenic induction, the cells were stained by oil red O and Alizarin Red. The neuronal induced cells were in the growth plateau and had special forms of neurons. In the presence of BMP4, the inner ear genes NF-M, Neurog1, GluR4, NeuroD, Calretinin, NeuN, Tau, and GATA3 were up-regulated in MSCs. Conclusions: MSCs have the capacity to differentiate into auditory neuron-like cells in vitro. As an effective inducer, BMP4 may play a key role in transdifferentiation.}, language = {en} } @article{SharkovskaReichetzederAlteretal.2014, author = {Sharkovska, Yuliya and Reichetzeder, Christoph and Alter, Markus L. and Tsuprykov, Oleg and Bachmann, Sebastian and Secher, Thomas and Klein, Thomas and Hocher, Berthold}, title = {Blood pressure and glucose independent renoprotective effects of dipeptidyl peptidase-4 inhibition in a mouse model of type-2 diabetic nephropathy}, series = {Journal of hypertension}, volume = {32}, journal = {Journal of hypertension}, number = {11}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {0263-6352}, doi = {10.1097/HJH.0000000000000328}, pages = {2211 -- 2223}, year = {2014}, abstract = {Background: Despite the beneficial effects of type 4 dipeptidyl peptidase (DPP-4) inhibitors on glucose levels, its effects on diabetic nephropathy remain unclear. Method: This study examined the long-term renoprotective effects of DPP-4 inhibitor linagliptin in db/db mice, a model of type 2 diabetes. Results were compared with the known beneficial effects of renin-angiotensin system blockade by enalapril. Ten-week-old male diabetic db/db mice were treated for 3 months with either vehicle (n = 10), 3 mg linagliptin/kg per day (n = 8), or 20 mg enalapril/kg per day (n = 10). Heterozygous db/m mice treated with vehicle served as healthy controls (n = 8). Results: Neither linagliptin nor enalapril had significant effects on the parameters of glucose metabolism or blood pressure in diabetic db/db mice. However, linagliptin treatment reduced albuminuria and attenuated kidney injury. In addition, expression of podocyte marker podocalyxin was normalized. We also analysed DPP-4 expression by immunofluorescence in human kidney biopsies and detected upregulation of DPP-4 in the glomeruli of patients with diabetic nephropathy, suggesting that our findings might be of relevance for human kidney disease as well. Conclusion: Treatment with DPP-4 inhibitor linagliptin delays the progression of diabetic nephropathy damage in a glucose-independent and blood-pressure-independent manner. The observed effects may be because of the attenuation of podocyte injury and inhibition of myofibroblast transformation.}, language = {en} } @article{HocherHeimerlSlowinskietal.2011, author = {Hocher, Berthold and Heimerl, Dirk and Slowinski, Torsten and Godes, Michael and Halle, Horst and Priem, Friedrich and Pfab, Thiemo}, title = {Birthweight and Fetal Glycosylated Hemoglobin at Birth in Newborns Carrying the GLUT1 XbaI Gene Polymorphism}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {57}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {9-10}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, pages = {651 -- 657}, year = {2011}, abstract = {Background: Low birthweight is an independent risk factor of glucose intolerance and type 2 diabetes in later life. Genetically determined insulin resistance and subsequently impaired glucose uptake might explain both reduced fetal growth and elevated blood glucose. The glucose transporter 1 (GLUT!) plays an important role for fetal glucose uptake as well as for maternal-fetal glucose transfer, and it has been associated with insulin resistance in adults. The present study hypothesized that the common fetal GLUT1 XbaI polymorphism might reduce fetal insulin sensitivity and/or glucose supply in utero, thus affecting fetal blood glucose and fetal growth. Methods: A genetic association study was conducted at the obstetrics department of the Charite University Hospital, Berlin, Germany. 119.1 white women were included after delivery, and all newborns were genotyped for the GLUT1 XbaI polymorphism. Total glycosylated hemoglobin was quantified, serving as a surrogate of glycemia during the last weeks of pregnancy. Results: The analysis of this large population showed no significant differences in fetal glycosylated hemoglobin or birthweight for the different fetal GLUT1 XbaI genotypes. Only newborns carrying the mutated allele show the previously published inverse association between birthweight and glycosylated hemoglobin. Conclusions: The results suggest that there is no prenatal effect of the fetal GLUT1 XbaI polymorphism on fetal insulin sensitivity, intrauterine fetal glucose supply or fetal growth. However, the polymorphism seems to modulate the inverse interaction between birthweight and fetal glycemia.}, language = {en} } @article{LuoChenZengetal.2018, author = {Luo, Ting and Chen, Xiaoyi and Zeng, Shufei and Guan, Baozhang and Hu, Bo and Meng, Yu and Liu, Fanna and Wong, Taksui and Lu, Yongpin and Yun, Chen and Hocher, Berthold and Yin, Lianghong}, title = {Bioinformatic identification of key genes and analysis of prognostic values in clear cell renal cell carcinoma}, series = {Oncology Letters}, volume = {16}, journal = {Oncology Letters}, number = {2}, publisher = {Spandidos publ LTD}, address = {Athens}, issn = {1792-1074}, doi = {10.3892/ol.2018.8842}, pages = {1747 -- 1757}, year = {2018}, abstract = {The present study aimed to identify new key genes as potential biomarkers for the diagnosis, prognosis or targeted therapy of clear cell renal cell carcinoma (ccRCC). Three expression profiles (GSE36895, GSE46699 and GSE71963) were collected from Gene Expression Omnibus. GEO2R was used to identify differentially expressed genes (DEGs) in ccRCC tissues and normal samples. The Database for Annotation, Visualization and Integrated Discovery was utilized for functional and pathway enrichment analysis. STRING v10.5 and Molecular Complex Detection were used for protein-protein interaction (PPI) network construction and module analysis, respectively. Regulation network analyses were performed with the WebGestal tool. UALCAN web-portal was used for expression validation and survival analysis of hub genes in ccRCC patients from The Cancer Genome Atlas (TCGA). A total of 65 up- and 164 downregulated genes were identified as DEGs. DEGs were enriched with functional terms and pathways compactly related to ccRCC pathogenesis. Seventeen hub genes and one significant module were filtered out and selected from the PPI network. The differential expression of hub genes was verified in TCGA patients. Kaplan-Meier plot showed that high mRNA expression of enolase 2 (ENO2) was associated with short overall survival in ccRCC patients (P=0.023). High mRNA expression of cyclin D1 (CCND1) (P<0.001), fms related tyrosine kinase 1 (FLT1) (P=0.004), plasminogen (PLG) (P<0.001) and von Willebrand factor (VWF) (P=0.008) appeared to serve as favorable factors in survival. These findings indicate that the DEGs may be key genes in ccRCC pathogenesis and five genes, including ENO2, CCND1, PLT1, PLG and VWF, may serve as potential prognostic biomarkers in ccRCC.}, language = {en} } @article{DwiPutraReichetzederHasanetal.2020, author = {Dwi Putra, Sulistyo Emantoko and Reichetzeder, Christoph and Hasan, Ahmed Abdallah Abdalrahman Mohamed and Slowinski, Torsten and Chu, Chang and Kr{\"a}mer, Bernhard K. and Kleuser, Burkhard and Hocher, Berthold}, title = {Being born large for gestational age is associated with increased global placental DNA methylation}, series = {Scientific Reports}, volume = {10}, journal = {Scientific Reports}, number = {1}, publisher = {Springer Nature}, address = {London}, issn = {2045-2322}, doi = {10.1038/s41598-020-57725-0}, pages = {1 -- 10}, year = {2020}, abstract = {Being born small (SGA) or large for gestational age (LGA) is associated with adverse birth outcomes and metabolic diseases in later life of the offspring. It is known that aberrations in growth during gestation are related to altered placental function. Placental function is regulated by epigenetic mechanisms such as DNA methylation. Several studies in recent years have demonstrated associations between altered patterns of DNA methylation and adverse birth outcomes. However, larger studies that reliably investigated global DNA methylation are lacking. The aim of this study was to characterize global placental DNA methylation in relationship to size for gestational age. Global DNA methylation was assessed in 1023 placental samples by LC-MS/MS. LGA offspring displayed significantly higher global placental DNA methylation compared to appropriate for gestational age (AGA; p<0.001). ANCOVA analyses adjusted for known factors impacting on DNA methylation demonstrated an independent association between placental global DNA methylation and LGA births (p<0.001). Tertile stratification according to global placental DNA methylation levels revealed a significantly higher frequency of LGA births in the third tertile. Furthermore, a multiple logistic regression analysis corrected for known factors influencing birth weight highlighted an independent positive association between global placental DNA methylation and the frequency of LGA births (p=0.001).}, language = {en} } @article{LiWangChenetal.2012, author = {Li, Jian and Wang, Zi-Neng and Chen, You-Peng and Dong, Yun-Peng and Mao, Xiao-Min and Hocher, Berthold}, title = {Association of fetal but not maternal P-glycoprotein C3435T polymorphism with fetal growth and birth weight, a possible risk factor for cardiovascular diseases in later life}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {9-10}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2012.110920}, pages = {1085 -- 1089}, year = {2012}, abstract = {Background: The multidrug transporter P-glycoprotein (PGP) is expressed in the human placenta. In particular the C3435T ABCB1 polymorphism was associated with altered tissue expression of PGP in the human placenta. However, the potential functional impact of this polymorphism on the offspring is unknown so far. Methods: We analyzed the impact of the ABCB1/C3435T polymorphism on fetal growth in 262 mother/child pairs. Fetal growth was assessed by differential ultrasound examination of the fetal body prior to birth and by measuring birth weight. Results: The maternal ABCB1/C3435T polymorphism showed no trend for an association with birth weight or any ultrasound parameter describing late gestational fetal body shape. Genotyping the newborns, however, demonstrated that newborns carrying two copies of the T allele had a birth weight of 3176.39 g, whereas CT and CC newborns had a birth weight of 3345.04 g (p = 0.022). Adjusting for gestational age at delivery, child's gender, maternal BM1, maternal age and body weight at delivery confirmed this finding (p = 0.009). Considering gestational day of late ultrasound examination, gestational age at delivery, child's gender, maternal BMI, maternal age and maternal body weight at delivery, the fetal ABCB1/C3435T genotype revealed likewise a significant negative correlation with abdominal diameter and abdominal circumference (R-2 = 0.538, p = 0.010 and R-2 = 0.534, p = 0.005, respectively). Conclusions: Low birth weight may be a risk factor for cardiovascular diseases in later life. The fetal ABCB1/C3435T gene polymorphism may contribute to this risk. Since PGP controls transport of various biological agents, we suggest that PGP is involved in the transport of biological agents to the fetus that are important for normal fetal growth.}, language = {en} } @article{YangLaiDengetal.2014, author = {Yang, Fang and Lai, Xinlong and Deng, Li and Liu, Xiaoxiao and Li, Jian and Zeng, Shuixiu and Zhang, Cheng and Hocher, Carl-Friedrich and Hocher, Berthold}, title = {Association of endothelin-1 gene polymorphisms with the clinical phenotype in primary nephrotic syndrome of children}, series = {Life sciences : molecular, cellular and functional basis of therapy}, volume = {118}, journal = {Life sciences : molecular, cellular and functional basis of therapy}, number = {2}, publisher = {Elsevier}, address = {Oxford}, issn = {0024-3205}, doi = {10.1016/j.lfs.2014.04.010}, pages = {446 -- 450}, year = {2014}, abstract = {Aims:This study aims to investigate the relationship between plasma endothelin-1 (ET-1) concentrations, ET-1 gene polymorphisms in loci rs5370, rs1630736, 3A/4A and clinical features of primary nephrotic syndrome (NS) in children. Materials and methods: Thirty-six children with primary NS were selected as case group, and 94 healthy children were selected as control group. All subjects were genotyped for three single nucleotide polymorphisms (SNPs) (rs5370, rs10478694 [3A4A) and rs 1630736) in the ET-1 gene by gene sequencing. The plasma ET-1 concentrations were measured using a radio-immunoassay. Key findings: Plasma ET-1 concentrations were higher in NS patients (P = 0.007) as compared to healthy children. The allele frequencies between control and NS patients were significantly different only with respect to the rs10478694 SNP of the ET-1 gene. The allele frequencies between control and NS patients for the rs5370 SNP showed a trend towards difference (P = 0.057). Plasma cholesterol in NS patients is associated with both: the Cl genotype in locus rs5370 and the 3A4A genotype in locus rs10478694 (P < 0.05 in both cases). Significance: The ET systems might play a disease modifying role in pediatric NS. Plasma cholesterol, a hallmark of NS. seems to be associated with genetic variations within the human ET-1 gene. (C) 2014 Elsevier Inc. All rights reserved.}, language = {en} } @article{PutraNeuberReichetzederetal.2014, author = {Putra, Sulistyo Emantoko Dwi and Neuber, Corinna and Reichetzeder, Christoph and Hocher, Berthold and Kleuser, Burkhard}, title = {Analysis of genomic DNA methylation levels in human placenta using liquid Chromatography-Electrospray ionization tandem mass spectrometry}, series = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, volume = {33}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, number = {4}, publisher = {Karger}, address = {Basel}, issn = {1015-8987}, doi = {10.1159/000358666}, pages = {945 -- 952}, year = {2014}, abstract = {Background: DNA-methylation is a common epigenetic tool which plays a crucial role in gene regulation and is essential for cell differentiation and embryonic development. The placenta is an important organ where gene activity can be regulated by epigenetic DNA modifications, including DNA methylation. This is of interest as, the placenta is the interface between the fetus and its environment, the mother. Exposure to environmental toxins and nutrition during pregnancy may alter DNA methylation of the placenta and subsequently placental function and as a result the phenotype of the offspring. The aim of this study was to develop a reliable method to quantify DNA methylation in large clinical studies. This will be a tool to analyze the degree of DNA methylation in the human placenta in relationship to clinical readouts. Methods: Liquid chromatography-electrospray ionization/multi-stage mass spectrometry (LC-ESI/MS/MS) technique was used for the quantification of the 5dmC/dG ratio in placentas from 248 healthy pregnancies. We were able to demonstrate that this method is a reliable and stable way to determine global placental DNA methylation in large clinical trials. Results/Conclusion: The degree of placental DNA methylation seen in our pilot study varies substantially from 2\% to 5\%. The clinical implications of this variation need to be demonstrated in adequately powered large studies.}, language = {en} } @article{VignonZellwegerRahnenfuehrerTheuringetal.2012, author = {Vignon-Zellweger, Nicolas and Rahnenf{\"u}hrer, Jan and Theuring, Franz and Hocher, Berthold}, title = {Analysis of cardiac and renal endothelin receptors by in situ hybridization in mice}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {9-10}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2012.120216}, pages = {939 -- 949}, year = {2012}, abstract = {Background: Endothelin-1 (ET-1) is a multifunctional peptide, which is implicated in the renal and cardiac physicology as well as in many pathologies of these systems. ET-1's actions take place after the activation of two receptors: ETA and ETB. The expression of these receptors may be modulated during the pathologic process. The analysis of the distribution and level of expression of the receptors in animal models is therefore crucial. Methods: We developed a protocol for non-radioactive in situ hybridization for the mRNA of the two endothelin receptors on paraffin-embedded tissue using digoxigenin-labeled RNA probes. Results: In heart and kidney, the staining was reliable and specific. In a mouse model for endothelin/nitric oxide imbalance, cardiac ETB expression was reduced. The distribution of the receptors was in accordance with the actual knowledge. Differences in cell specific expression are discussed. Conclusions: We developed a protocol for the in situ hybridization of the endothelin receptors in mice. Given that the endothelin system is implicated in the development of many diseases, we believe that this protocol may be useful for a number of future preclinical studies.}, language = {en} } @article{GlosseFegerMutigetal.2018, author = {Glosse, Philipp and Feger, Martina and Mutig, Kerim and Chen, Hong and Hirche, Frank and Hasan, Ahmed Abdallah Abdalrahman Mohamed and Gaballa, Mohamed Mahmoud Salem Ahmed and Hocher, Berthold and Lang, Florian and F{\"o}ller, Michael}, title = {AMP-activated kinase is a regulator of fibroblast growth factor 23 production}, series = {Kidney international : official journal of the International Society of Nephrology}, volume = {94}, journal = {Kidney international : official journal of the International Society of Nephrology}, number = {3}, publisher = {Elsevier}, address = {New York}, issn = {0085-2538}, doi = {10.1016/j.kint.2018.03.006}, pages = {491 -- 501}, year = {2018}, abstract = {Fibroblast growth factor 23 (FGF23) is a proteohormone regulating renal phosphate transport and vitamin D metabolism as well as inducing left heart hypertrophy. FGF23-deficient mice suffer from severe tissue calcification, accelerated aging and a myriad of aging-associated diseases. Bone cells produce FGF23 upon store-operated calcium ion entry (SOCE) through the calcium selective ion channel Orai1. AMP-activated kinase (AMPK) is a powerful energy sensor helping cells survive states of energy deficiency, and AMPK down-regulates Orai1. Here we investigated the role of AMPK in FGF23 production. Fgf23 gene transcription was analyzed by qRT-PCR and SOCE by fluorescence optics in UMR106 osteoblast-like cells while the serum FGF23 concentration and phosphate metabolism were assessed in AMPKa1-knockout and wild-type mice. The AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) down-regulated, whereas the AMPK inhibitor, dorsomorphin dihydrochloride (compound C) and AMPK gene silencing induced Fgf23 transcription. AICAR decreased membrane abundance of Orai1 and SOCE. SOCE inhibitors lowered Fgf23 gene expression induced by AMPK inhibition. AMPKa1-knockout mice had a higher serum FGF23 concentration compared to wild-type mice. Thus, AMPK participates in the regulation of FGF23 production in vitro and in vivo. The inhibitory effect of AMPK on FGF23 production is at least in part mediated by Orai1-involving SOCE.}, language = {en} } @article{HeunischChaykovskavonEinemetal.2017, author = {Heunisch, Fabian and Chaykovska, Lyubov and von Einem, Gina and Alter, Markus and Dschietzig, Thomas and Kretschmer, Axel and Kellner, Karl-Heinz and Hocher, Berthold}, title = {ADMA predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus undergoing coronary angiography}, series = {Medicine}, volume = {96}, journal = {Medicine}, number = {6}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {0025-7974}, doi = {10.1097/MD.0000000000006065}, pages = {7}, year = {2017}, abstract = {Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of the nitric oxide (NO)-synthase and a biomarker of endothelial dysfunction (ED). ED plays an important role in the pathogenesis of contrast-induced nephropathy (CIN). The aim of our study was to evaluate serum ADMA concentration as a biomarker of an acute renal damage during the follow-up of 90 days after contrast medium (CM) application. Blood samples were obtained from 330 consecutive patients with diabetes mellitus or mild renal impairment immediately before, 24 and 48 hours after the CM application for coronary angiography. The patients were followed for 90 days. The composite endpoints were major adverse renal events (MARE) defined as occurrence of death, initiation of dialysis, or a doubling of serum creatinine concentration. Overall, ADMA concentration in plasma increased after CM application, although, there was no differences between ADMA levels in patients with and without CIN. ADMA concentration 24 hours after the CM application was predictive for dialysis with a specificity of 0.889 and sensitivity of 0.653 at values higher than 0.71 mu mol/L (area under the curve: 0.854, 95\% confidential interval: 0.767-0.941, P<0.001). This association remained significant in multivariate Cox regression models adjusted for relevant factors of long-term renal outcome. 24 hours after the CM application, ADMA concentration in plasma was predictive for MARE with a specificity of 0.833 and sensitivity of 0.636 at a value of more than 0.70 mu mol/L (area under the curve: 0.750, 95\% confidence interval: 0.602-0.897, P=0.004). Multivariate logistic regression analysis confirmed that ADMA and anemia were significant predictors of MARE. Further analysis revealed that increased ADMA concentration in plasma was highly significant predictor of MARE in patients with CIN. Moreover, patients with CIN and MARE had the highest plasma ADMA levels 24 hours after CM exposure in our study cohort. The impact of ADMA on MARE was independent of such known CIN risk factors as anemia, pre-existing renal failure, pre-existing heart failure, and diabetes. ADMA concentration in plasma is a promising novel biomarker of major contrast-induced nephropathy-associated events 90 days after contrast media exposure.}, language = {en} } @article{Hocher2010, author = {Hocher, Berthold}, title = {Adenosine A1 receptor antagonists in clinical research and development}, issn = {0085-2538}, doi = {10.1038/Ki.2010.204}, year = {2010}, abstract = {Selective adenosine A1 receptor antagonists targeting renal microcirculation are novel pharmacologic agents that are currently under development for the treatment of acute heart failure as well as for chronic heart failure. Despite several studies showing improvement of renal function and/or increased diuresis with adenosine A1 antagonists, particularly in chronic heart failure, these findings were not confirmed in a large phase III trial in acute heart failure patients. However, lessons can be learned from these and other studies, and there might still be a potential role for the clinical use of adenosine A1 antagonists. We review the role of adenosine A1 receptors in the regulation of renal function, and emerging data regarding the safety and efficacy of A1 adenosine receptor antagonists based on all available completed and reported clinical trials using A1 adenosine receptor antagonists. The majority of trials were done in heart failure patients. However, there is clear clinical evidence for a role of this new class in hepatorenal syndrome, hypotension on dialysis, and radiocontrast media-induced nephropathy.}, language = {en} } @article{HeLiuLuetal.2017, author = {He, Jing and Liu, Zhi-Wei and Lu, Yong-Ping and Li, Tao-Yuan and Liang, Xu-Jing and Arck, Petra and Huang, Si-Min and Hocher, Berthold and Chen, You-Peng}, title = {A systematic review and meta-analysis of influenza a virus infection during pregnancy associated with an increased risk for stillbirth and low birth weight}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft}, volume = {42}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft}, number = {2}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000477221}, pages = {232 -- 243}, year = {2017}, abstract = {Background/Aims: Impaired pregnancy outcomes, such as low birth weight are associated with increased disease risk in later life, however little is known about the impact of common infectious diseases during pregnancy on birth weight. The study had two aims: a) to investigate risk factors of influenza virus infection during pregnancy, and b) to analyze the impact of influenza virus infection on pregnancy outcome, especially birth weight. Methods: Prospective and retrospective observational studies found in PubMed, MEDLINE, Embase, Google Scholar, and WangFang database were included in this meta analysis. Data of included studies was extracted and analyzed by the RevMan software. Results: Pregnant women with anemia (P=0.004, RR=1.46, 95\% CI: 1.13-1.88), obesity (P<0.00001, RR=1.35, 95\% CI: 1.25-1.46) and asthma (P<0.00001, RR=1.99, 95\% CI: 1.67-2.37) had higher rates of influenza virus infection. Regarding birth outcomes, influenza A virus infection did not affect the likelihood for cesarean section. Mothers with influenza had a higher rate of stillbirth (P=0.04, RR=2.36, 95\% CI: 1.05-5.31), and their offspring had low 5-minute APGR Scores (P=0.009, RR=1.39, 95\% CI: 1.08-1.79). Furthermore, the rate for birth weight < 2500g (P=0.04, RR=1.71, 95\% CI: 1.03-2.84) was increased. Conclusion: Results of this study showed that anemia, asthma and obesity during pregnancy are risk factors influenza A virus infection during pregnancy. Moreover, gestational influenza A infection impairs pregnancy outcomes and increases the risk for low birth weight, a known risk factor for later life disease susceptibility.}, language = {en} } @article{vanderValkKreinerMollerKooijmanetal.2015, author = {van der Valk, Ralf J. P. and Kreiner-Moller, Eskil and Kooijman, Marjolein N. and Guxens, Monica and Stergiakouli, Evangelia and Saaf, Annika and Bradfield, Jonathan P. and Geller, Frank and Hayes, M. Geoffrey and Cousminer, Diana L. and Koerner, Antje and Thiering, Elisabeth and Curtin, John A. and Myhre, Ronny and Huikari, Ville and Joro, Raimo and Kerkhof, Marjan and Warrington, Nicole M. and Pitkanen, Niina and Ntalla, Ioanna and Horikoshi, Momoko and Veijola, Riitta and Freathy, Rachel M. and Teo, Yik-Ying and Barton, Sheila J. and Evans, David M. and Kemp, John P. and St Pourcain, Beate and Ring, Susan M. and Smith, George Davey and Bergstrom, Anna and Kull, Inger and Hakonarson, Hakon and Mentch, Frank D. and Bisgaard, Hans and Chawes, Bo Lund Krogsgaard and Stokholm, Jakob and Waage, Johannes and Eriksen, Patrick and Sevelsted, Astrid and Melbye, Mads and van Duijn, Cornelia M. and Medina-Gomez, Carolina and Hofman, Albert and de Jongste, Johan C. and Taal, H. Rob and Uitterlinden, Andre G. and Armstrong, Loren L. and Eriksson, Johan and Palotie, Aarno and Bustamante, Mariona and Estivill, Xavier and Gonzalez, Juan R. and Llop, Sabrina and Kiess, Wieland and Mahajan, Anubha and Flexeder, Claudia and Tiesler, Carla M. T. and Murray, Clare S. and Simpson, Angela and Magnus, Per and Sengpiel, Verena and Hartikainen, Anna-Liisa and Keinanen-Kiukaanniemi, Sirkka and Lewin, Alexandra and Alves, Alexessander Da Silva Couto and Blakemore, Alexandra I. F. and Buxton, Jessica L. and Kaakinen, Marika and Rodriguez, Alina and Sebert, Sylvain and Vaarasmaki, Marja and Lakka, Timo and Lindi, Virpi and Gehring, Ulrike and Postma, Dirkje S. and Ang, Wei and Newnham, John P. and Lyytikainen, Leo-Pekka and Pahkala, Katja and Raitakari, Olli T. and Panoutsopoulou, Kalliope and Zeggini, Eleftheria and Boomsma, Dorret I. and Groen-Blokhuis, Maria and Ilonen, Jorma and Franke, Lude and Hirschhorn, Joel N. and Pers, Tune H. and Liang, Liming and Huang, Jinyan and Hocher, Berthold and Knip, Mikael and Saw, Seang-Mei and Holloway, John W. and Melen, Erik and Grant, Struan F. A. and Feenstra, Bjarke and Lowe, William L. and Widen, Elisabeth and Sergeyev, Elena and Grallert, Harald and Custovic, Adnan and Jacobsson, Bo and Jarvelin, Marjo-Riitta and Atalay, Mustafa and Koppelman, Gerard H. and Pennell, Craig E. and Niinikoski, Harri and Dedoussis, George V. and Mccarthy, Mark I. and Frayling, Timothy M. and Sunyer, Jordi and Timpson, Nicholas J. and Rivadeneira, Fernando and Bonnelykke, Klaus and Jaddoe, Vincent W. V.}, title = {A novel common variant in DCST2 is associated with length in early life and height in adulthood}, series = {Human molecular genetics}, volume = {24}, journal = {Human molecular genetics}, number = {4}, publisher = {Oxford Univ. Press}, address = {Oxford}, organization = {Early Genetics Lifecourse, Genetic Invest ANthropometric, Early Growth Genetics EGG}, issn = {0964-6906}, doi = {10.1093/hmg/ddu510}, pages = {1155 -- 1168}, year = {2015}, abstract = {Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 x 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; beta = 0.046, SE = 0.008, P = 2.46 x 10(-8), explained variance = 0.05\%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 x 10(-4)) and adult height (N = 127 513; P = 1.45 x 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13\% of variance in birth length. The same SNPs explained 2.95\% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.}, language = {en} }