TY - JOUR A1 - Zebger-Gong, Hong A1 - Mueller, Dominik A1 - Diercke, Michaela A1 - Haffner, Dieter A1 - Hocher, Berthold A1 - Verberckmoes, Steven A1 - Schmidt, Sven A1 - D'Haese, Patrick C. A1 - Querfeld, Uwe T1 - 1,25-Dihydroxyvitamin D-3-induced aortic calcifications in experimental uremia: up-regulation of osteoblast markers, calcium-transporting proteins and osterix JF - Journal of hypertension N2 - Background and objective Whether treatment with vitamin D receptor activators contributes to cardiovascular disease in patients with chronic kidney disease is a matter of debate. We studied mechanisms involved in vitamin D-related vascular calcifications in vivo and in vitro. Methods Aortic calcifications were induced in subtotally nephrectomized (SNX) rats by treatment with a high dose (0.25 mu g/kg per day) of 1,25-dihydroxyvitamin D-3 (calcitriol) given for 6 weeks. Likewise, primary rat vascular smooth muscle cells (VSMCs) were incubated with calcitriol at concentrations ranging from 10(-11) to 10(-7) mol/l. Immunohistochemistry revealed that the aortic expression of osteopontin, osteocalcin and bone sialoprotein was significantly increased in calcitriol-treated SNX rats compared to untreated SNX controls. In addition, aortic expression of the transient receptor potential vanilloid calcium channel 6 (TRPV6) and calbindin D9k was significantly up-regulated by treatment with calcitriol. Furthermore, calcitriol significantly increased expression of the osteogenic transcription factor osterix. In-vitro studies showed similar results, confirming that these effects could be attributed to treatment with calcitriol. Conclusions High-dose calcitriol treatment induces an osteoblastic phenotype in VSMC both in SNX rats and in vitro, associated with up-regulation of proteins regulating mineralization and calcium transport, and of the osteogenic transcription factor osterix. KW - calbindin D9k KW - calcitriol KW - calcium transport KW - osteoblast KW - osterix KW - TRPV5 KW - TRPV6 KW - vascular calcification Y1 - 2011 U6 - https://doi.org/10.1097/HJH.0b013e328340aa30 SN - 0263-6352 VL - 29 IS - 2 SP - 339 EP - 348 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Li, Jian A1 - Chen, You-Peng A1 - Wang, Zi-Neng A1 - Liu, Tie-Bin A1 - Chen, Dan A1 - Dong, Yun-Peng A1 - Hocher, Berthold T1 - A functional fetal HSD11B2[CA]n microsatellite polymorphism is associated with maternal serum cortisol concentrations in pregnant women JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie N2 - Background/Aims: Cortisol plays an important role during pregnancy. It controls maternal glucose metabolism and fetal development. Cortisol metabolism is partially controlled by the 11b-HSD2. This enzyme is expressed in the kidney and human placenta. The activity of the enzyme is partially controlled by functional polymorphisms: the HSD11B2[CA]n microsatellite polymorphism. The impact of this functional gene polymorphism on cortisol metabolism and potential effects on the newborn's is unknown so far. Methods: In the current prospective birth cohort study in southern Asia, we analyzed the association of the HSD11B2[CA]n microsatellite polymorphisms in 187 mothers and their newborn's on maternal and newborn's serum cortisol concentrations. Results: Using multivariable regression analyses considering known confounding ( gestational age, newborn's gender, the labor uterine contraction states and the timing during the day of blood taking), we showed that the fetal HSD11B2[CA]n microsatellite polymorphisms in the first intron was related to maternal cortisol concentration ( R2=0.26, B=96.27, p=0.007), whereas as the newborn's cortisol concentrations were independent of fetal and maternal HSD11B2[CA] n microsatellite polymorphism. Conclusions: Our study showed for the first time that the fetal HSD11B2[CA]n microsatellite polymorphism of the HSD11B2 gene in healthy uncomplicated human pregnancy is associated with maternal cortisol concentration. This indicates that fetal genes controlling cortisol metabolism may affect maternal cortisol concentration and hence physiology in healthy pregnant women. KW - Pregnancy KW - Placenta KW - Cortisol vertical bar metabolism KW - 11 beta-hydroxysteroid dehydrogenase 2 KW - HSD11B2[CA]n polymorphism Y1 - 2013 U6 - https://doi.org/10.1159/000355761 SN - 1420-4096 SN - 1423-0143 VL - 38 IS - 1 SP - 132 EP - 141 PB - Karger CY - Basel ER - TY - JOUR A1 - van der Valk, Ralf J. P. A1 - Kreiner-Moller, Eskil A1 - Kooijman, Marjolein N. A1 - Guxens, Monica A1 - Stergiakouli, Evangelia A1 - Saaf, Annika A1 - Bradfield, Jonathan P. A1 - Geller, Frank A1 - Hayes, M. Geoffrey A1 - Cousminer, Diana L. A1 - Koerner, Antje A1 - Thiering, Elisabeth A1 - Curtin, John A. A1 - Myhre, Ronny A1 - Huikari, Ville A1 - Joro, Raimo A1 - Kerkhof, Marjan A1 - Warrington, Nicole M. A1 - Pitkanen, Niina A1 - Ntalla, Ioanna A1 - Horikoshi, Momoko A1 - Veijola, Riitta A1 - Freathy, Rachel M. A1 - Teo, Yik-Ying A1 - Barton, Sheila J. A1 - Evans, David M. A1 - Kemp, John P. A1 - St Pourcain, Beate A1 - Ring, Susan M. A1 - Smith, George Davey A1 - Bergstrom, Anna A1 - Kull, Inger A1 - Hakonarson, Hakon A1 - Mentch, Frank D. A1 - Bisgaard, Hans A1 - Chawes, Bo Lund Krogsgaard A1 - Stokholm, Jakob A1 - Waage, Johannes A1 - Eriksen, Patrick A1 - Sevelsted, Astrid A1 - Melbye, Mads A1 - van Duijn, Cornelia M. A1 - Medina-Gomez, Carolina A1 - Hofman, Albert A1 - de Jongste, Johan C. A1 - Taal, H. Rob A1 - Uitterlinden, Andre G. A1 - Armstrong, Loren L. A1 - Eriksson, Johan A1 - Palotie, Aarno A1 - Bustamante, Mariona A1 - Estivill, Xavier A1 - Gonzalez, Juan R. A1 - Llop, Sabrina A1 - Kiess, Wieland A1 - Mahajan, Anubha A1 - Flexeder, Claudia A1 - Tiesler, Carla M. T. A1 - Murray, Clare S. A1 - Simpson, Angela A1 - Magnus, Per A1 - Sengpiel, Verena A1 - Hartikainen, Anna-Liisa A1 - Keinanen-Kiukaanniemi, Sirkka A1 - Lewin, Alexandra A1 - Alves, Alexessander Da Silva Couto A1 - Blakemore, Alexandra I. F. A1 - Buxton, Jessica L. A1 - Kaakinen, Marika A1 - Rodriguez, Alina A1 - Sebert, Sylvain A1 - Vaarasmaki, Marja A1 - Lakka, Timo A1 - Lindi, Virpi A1 - Gehring, Ulrike A1 - Postma, Dirkje S. A1 - Ang, Wei A1 - Newnham, John P. A1 - Lyytikainen, Leo-Pekka A1 - Pahkala, Katja A1 - Raitakari, Olli T. A1 - Panoutsopoulou, Kalliope A1 - Zeggini, Eleftheria A1 - Boomsma, Dorret I. A1 - Groen-Blokhuis, Maria A1 - Ilonen, Jorma A1 - Franke, Lude A1 - Hirschhorn, Joel N. A1 - Pers, Tune H. A1 - Liang, Liming A1 - Huang, Jinyan A1 - Hocher, Berthold A1 - Knip, Mikael A1 - Saw, Seang-Mei A1 - Holloway, John W. A1 - Melen, Erik A1 - Grant, Struan F. A. A1 - Feenstra, Bjarke A1 - Lowe, William L. A1 - Widen, Elisabeth A1 - Sergeyev, Elena A1 - Grallert, Harald A1 - Custovic, Adnan A1 - Jacobsson, Bo A1 - Jarvelin, Marjo-Riitta A1 - Atalay, Mustafa A1 - Koppelman, Gerard H. A1 - Pennell, Craig E. A1 - Niinikoski, Harri A1 - Dedoussis, George V. A1 - Mccarthy, Mark I. A1 - Frayling, Timothy M. A1 - Sunyer, Jordi A1 - Timpson, Nicholas J. A1 - Rivadeneira, Fernando A1 - Bonnelykke, Klaus A1 - Jaddoe, Vincent W. V. T1 - A novel common variant in DCST2 is associated with length in early life and height in adulthood JF - Human molecular genetics N2 - 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. Y1 - 2015 U6 - https://doi.org/10.1093/hmg/ddu510 SN - 0964-6906 SN - 1460-2083 VL - 24 IS - 4 SP - 1155 EP - 1168 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - He, Jing A1 - Liu, Zhi-Wei A1 - Lu, Yong-Ping A1 - Li, Tao-Yuan A1 - Liang, Xu-Jing A1 - Arck, Petra A1 - Huang, Si-Min A1 - Hocher, Berthold A1 - Chen, You-Peng T1 - A systematic review and meta-analysis of influenza a virus infection during pregnancy associated with an increased risk for stillbirth and low birth weight JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie ; official organ of the Deutsche Liga zur Bekämpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft N2 - 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. KW - Apgar score KW - Influenza virus KW - Offspring KW - Outcome KW - Pregnancy KW - Stillbirth KW - Birth weight Y1 - 2017 U6 - https://doi.org/10.1159/000477221 SN - 1420-4096 SN - 1423-0143 VL - 42 IS - 2 SP - 232 EP - 243 PB - Karger CY - Basel ER - TY - GEN A1 - Alter, Markus L. A1 - Ott, Ina A1 - von Websky, Karoline A1 - Tsuprykov, Oleg A1 - Sharkovska, Yuliya A1 - Krause-Relle, Katharina A1 - Raila, Jens A1 - Henze, Andrea A1 - Kretschmer, Axel A1 - Stasch, Johannes-Peter A1 - Hocher, Berthold T1 - Additional stimulation of sGC on top of standard treatment with ARB`s may offer a new therapeutic approach for the treatment of diabetic nephropathy resistant to ARB treatment alone T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Background Riociguat is the first of a new class of drugs, the soluble guanylate cyclase (sGC) stimulators. Riociguat has a dual mode of action: it sensitizes sGC to the body’s own NO and can also increase sGC activity in the absence of NO. The NO-sGC-pathway is impaired in many cardiovascular diseases such as heart failure, pulmonary hypertension and diabetic nephropathy (DN). DN leads to high cardiovascular morbidity and mortality. There is still a high unmet medical need. The urinary albumin excretion rate is a predictive biomarker for these clinical events. Therefore, we investigated the effect of riociguat, alone and in combination with the angiotensin II receptor antagonist (ARB) telmisartan on the progression of DN in diabetic eNOS knock out mice, a new model closely resembling human pathology. Methods Seventy-six male eNOS knockout C57BL/6J mice were divided into 4 groups after receiving intraperitoneal high-dose streptozotocin: telmisartan (1 mg/kg), riociguat (3 mg/kg), riociguat+telmisartan (3 and 1 mg/kg), and vehicle. Fourteen mice were used as non-diabetic controls. After 12 weeks, urine and blood were obtained and blood pressure measured. Glucose concentrations were highly increased and similar in all diabetic groups. Results Riociguat, alone (105.2 ± 2.5 mmHg; mean±SEM; n = 14) and in combination with telmisartan (105.0 ± 3.2 mmHg; n = 12), significantly reduced blood pressure versus diabetic controls (117.1 ± 2.2 mmHg; n = 14; p = 0.002 and p = 0.004, respectively), whereas telmisartan alone (111.2 ± 2.6 mmHg) showed a modest blood pressure lowering trend (p = 0.071; n = 14). The effects of single treatment with either riociguat (97.1 ± 15.7 µg/d; n = 13) or telmisartan (97.8 ± 26.4 µg/d; n = 14) did not significantly lower albumin excretion on its own (p = 0.067 and p = 0.101, respectively). However, the combined treatment led to significantly lower urinary albumin excretion (47.3 ± 9.6 µg/d; n = 12) compared to diabetic controls (170.8 ± 34.2 µg/d; n = 13; p = 0.004), and reached levels similar to non-diabetic controls (31.4 ± 10.1 µg/d, n = 12). Conclusion Riociguat significantly reduced urinary albumin excretion in diabetic eNOS knock out mice that were refractory to treatment with ARB’s alone. Patients with diabetic nephropathy refractory to treatment with ARB’s have the worst prognosis among all patients with diabetic nephropathy. Our data indicate that additional stimulation of sGC on top of standard treatment with ARB`s may offer a new therapeutic approach for patients with diabetic nephropathy resistant to ARB treatment. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 855 KW - pulmonary hypertension KW - diabetic nephropathy KW - diabetic control KW - telmisartan KW - guanylate cyclase Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-428250 SN - 1866-8372 IS - 855 ER - TY - JOUR A1 - Hocher, Berthold T1 - Adenosine A1 receptor antagonists in clinical research and development N2 - 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. Y1 - 2010 UR - http://www.nature.com/ki/index.html U6 - https://doi.org/10.1038/Ki.2010.204 SN - 0085-2538 ER - TY - JOUR A1 - Heunisch, Fabian A1 - Chaykovska, Lyubov A1 - von Einem, Gina A1 - Alter, Markus A1 - Dschietzig, Thomas A1 - Kretschmer, Axel A1 - Kellner, Karl-Heinz A1 - Hocher, Berthold T1 - ADMA predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus undergoing coronary angiography JF - Medicine N2 - 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. KW - asymmetric dimethylarginine (ADMA) KW - biomarkers of renal failure KW - contrast-induced nephropathy Y1 - 2017 U6 - https://doi.org/10.1097/MD.0000000000006065 SN - 0025-7974 SN - 1536-5964 VL - 96 IS - 6 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Glosse, Philipp A1 - Feger, Martina A1 - Mutig, Kerim A1 - Chen, Hong A1 - Hirche, Frank A1 - Hasan, Ahmed Abdallah Abdalrahman Mohamed A1 - Gaballa, Mohamed Mahmoud Salem Ahmed A1 - Hocher, Berthold A1 - Lang, Florian A1 - Föller, Michael T1 - AMP-activated kinase is a regulator of fibroblast growth factor 23 production JF - Kidney international : official journal of the International Society of Nephrology N2 - 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. KW - calcium KW - FGF23 KW - Klotho KW - Orai1 KW - phosphate KW - parathyroid hormone Y1 - 2018 U6 - https://doi.org/10.1016/j.kint.2018.03.006 SN - 0085-2538 SN - 1523-1755 VL - 94 IS - 3 SP - 491 EP - 501 PB - Elsevier CY - New York ER - TY - JOUR A1 - Vignon-Zellweger, Nicolas A1 - Rahnenführer, Jan A1 - Theuring, Franz A1 - Hocher, Berthold T1 - Analysis of cardiac and renal endothelin receptors by in situ hybridization in mice JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - 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. KW - Endothelin-1 KW - endothelin receptors KW - in situ hybridization KW - mouse Y1 - 2012 U6 - https://doi.org/10.7754/Clin.Lab.2012.120216 SN - 1433-6510 VL - 58 IS - 9-10 SP - 939 EP - 949 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Putra, Sulistyo Emantoko Dwi A1 - Neuber, Corinna A1 - Reichetzeder, Christoph A1 - Hocher, Berthold A1 - Kleuser, Burkhard T1 - Analysis of genomic DNA methylation levels in human placenta using liquid Chromatography-Electrospray ionization tandem mass spectrometry JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - 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. KW - Pregnancy KW - Placenta KW - Methylation KW - Global KW - LC-MS/MS KW - Fetal programming KW - Clinical Y1 - 2014 U6 - https://doi.org/10.1159/000358666 SN - 1015-8987 SN - 1421-9778 VL - 33 IS - 4 SP - 945 EP - 952 PB - Karger CY - Basel ER - TY - JOUR A1 - Yang, Fang A1 - Lai, Xinlong A1 - Deng, Li A1 - Liu, Xiaoxiao A1 - Li, Jian A1 - Zeng, Shuixiu A1 - Zhang, Cheng A1 - Hocher, Carl-Friedrich A1 - Hocher, Berthold T1 - Association of endothelin-1 gene polymorphisms with the clinical phenotype in primary nephrotic syndrome of children JF - Life sciences : molecular, cellular and functional basis of therapy N2 - 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. KW - Endothelin-1 KW - Gene polymorphism KW - Childhood nephrotic syndrome KW - Cholesterol Y1 - 2014 U6 - https://doi.org/10.1016/j.lfs.2014.04.010 SN - 0024-3205 SN - 1879-0631 VL - 118 IS - 2 SP - 446 EP - 450 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Li, Jian A1 - Wang, Zi-Neng A1 - Chen, You-Peng A1 - Dong, Yun-Peng A1 - Mao, Xiao-Min A1 - Hocher, Berthold T1 - 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 JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - 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. Y1 - 2012 U6 - https://doi.org/10.7754/Clin.Lab.2012.110920 SN - 1433-6510 VL - 58 IS - 9-10 SP - 1085 EP - 1089 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - GEN A1 - Dwi Putra, Sulistyo Emantoko A1 - Reichetzeder, Christoph A1 - Hasan, Ahmed Abdallah Abdalrahman Mohamed A1 - Slowinski, Torsten A1 - Chu, Chang A1 - Krämer, Bernhard K. A1 - Kleuser, Burkhard A1 - Hocher, Berthold T1 - Being born large for gestational age is associated with increased global placental DNA methylation T2 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - 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). T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1405 KW - fetal origins hypothesis KW - birth weight KW - repetitive elements KW - glucocorticoid receptor KW - nutrient transport KW - growth restriction KW - later health KW - pregnancy KW - genes KW - patterns Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-516289 SN - 1866-8372 IS - 1 ER - TY - JOUR A1 - Dwi Putra, Sulistyo Emantoko A1 - Reichetzeder, Christoph A1 - Hasan, Ahmed Abdallah Abdalrahman Mohamed A1 - Slowinski, Torsten A1 - Chu, Chang A1 - Krämer, Bernhard K. A1 - Kleuser, Burkhard A1 - Hocher, Berthold T1 - Being born large for gestational age is associated with increased global placental DNA methylation JF - Scientific Reports N2 - 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). KW - fetal origins hypothesis KW - birth weight KW - repetitive elements KW - glucocorticoid receptor KW - nutrient transport KW - growth restriction KW - later health KW - pregnancy KW - genes KW - patterns Y1 - 2020 U6 - https://doi.org/10.1038/s41598-020-57725-0 SN - 2045-2322 VL - 10 IS - 1 SP - 1 EP - 10 PB - Springer Nature CY - London ER - TY - JOUR A1 - Luo, Ting A1 - Chen, Xiaoyi A1 - Zeng, Shufei A1 - Guan, Baozhang A1 - Hu, Bo A1 - Meng, Yu A1 - Liu, Fanna A1 - Wong, Taksui A1 - Lu, Yongpin A1 - Yun, Chen A1 - Hocher, Berthold A1 - Yin, Lianghong T1 - Bioinformatic identification of key genes and analysis of prognostic values in clear cell renal cell carcinoma JF - Oncology Letters N2 - 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. KW - clear cell renal cell carcinoma KW - bioinformatics KW - differentially expressed genes KW - biomarkers KW - Kaplan-Meier plot Y1 - 2018 U6 - https://doi.org/10.3892/ol.2018.8842 SN - 1792-1074 SN - 1792-1082 VL - 16 IS - 2 SP - 1747 EP - 1757 PB - Spandidos publ LTD CY - Athens ER - TY - JOUR A1 - Chaykovska, Lyubov A1 - Tsuprykov, Oleg A1 - Hocher, Berthold T1 - Biomarkers for the prediction of mortality and morbidity in patients with renal replacement therapy JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - The mortality of end-stage renal disease (ESRD) patients on dialysis remains high despite great improvement of dialysis technologies in the past decades. These patients die due to infectious diseases (mainly sepsis), cardiovascular diseases such as myocardial infarction, heart failure, stroke, and, in particular, sudden cardiac death. End stage renal disease is a complex condition, where the failure of kidney function is accompanied by numerous metabolic changes affecting almost all organ systems of the human body. Many of the biomarker characteristics of the individually affected organ systems have been associated with adverse outcomes. These biomarkers are different in patients with ESRD compared to the general population in the prediction of morbidity and mortality. Biomarker research in this field should aim to identify patients at risk for the different disease entities. Traditional biomarkers such as CRP, BNP, and troponins as well as new biomarkers such as fetuin, CD 154, and relaxin were analyzed in patients on dialysis. We will include observational as well as prospective clinical trials in this review. Furthermore, we will also discuss proteomics biomarker studies. The article assess the potential diagnostic value of different biomarkers in daily clinical practice as well as their usefulness for clinical drug development in end stage renal disease patients. Y1 - 2011 SN - 1433-6510 VL - 57 IS - 7-8 SP - 455 EP - 467 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Hocher, Berthold A1 - Heimerl, Dirk A1 - Slowinski, Torsten A1 - Godes, Michael A1 - Halle, Horst A1 - Priem, Friedrich A1 - Pfab, Thiemo T1 - Birthweight and Fetal Glycosylated Hemoglobin at Birth in Newborns Carrying the GLUT1 XbaI Gene Polymorphism JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - 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. KW - GLUT1 XbaI gene polymorphism KW - birthweight KW - total glycosylated hemoglobin KW - insulin resistance KW - fetal programming Y1 - 2011 SN - 1433-6510 VL - 57 IS - 9-10 SP - 651 EP - 657 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Sharkovska, Yuliya A1 - Reichetzeder, Christoph A1 - Alter, Markus L. A1 - Tsuprykov, Oleg A1 - Bachmann, Sebastian A1 - Secher, Thomas A1 - Klein, Thomas A1 - Hocher, Berthold T1 - Blood pressure and glucose independent renoprotective effects of dipeptidyl peptidase-4 inhibition in a mouse model of type-2 diabetic nephropathy JF - Journal of hypertension N2 - 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. KW - diabetic nephropathy KW - DPP-4 inhibitors KW - linagliptin Y1 - 2014 U6 - https://doi.org/10.1097/HJH.0000000000000328 SN - 0263-6352 SN - 1473-5598 VL - 32 IS - 11 SP - 2211 EP - 2223 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Peng, Tao A1 - Zhu, Ganghua A1 - Dong, Yunpeng A1 - Zeng, Junjie A1 - Li, Wei A1 - Guo, Weiwei A1 - Chen, Yong A1 - Duan, Maoli A1 - Hocher, Berthold A1 - Xie, Dinghua T1 - BMP4: a possible key factor in differentiation of auditory neuron-like cells from bone-derived mesenchymal stromal cells JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - 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. KW - differentiation KW - auditory neurons KW - BMP4 Y1 - 2015 U6 - https://doi.org/10.7754/Clin.Lab.2015.150217 SN - 1433-6510 VL - 61 IS - 9 SP - 1171 EP - 1178 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - CHAP A1 - Sharkovska, Y. A1 - Pohl, K. K. A1 - Hocher, Berthold A1 - Dschietzig, T. T1 - Cardiac expression of relaxin and its receptor RXFP1 in rats with renovascular hypertension T2 - EUROPEAN HEART JOURNAL Y1 - 2013 SN - 0195-668X SN - 1522-9645 VL - 34 IS - 10 SP - 1056 EP - 1056 PB - OXFORD UNIV PRESS CY - OXFORD ER -