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 - Hasan, Ahmed Abdallah Abdalrahman Mohamed A1 - Hocher, Berthold T1 - Role of soluble and membrane-bound dipeptidyl peptidase-4 in diabetic nephropathy JF - Journal of Molecular Endocrinology N2 - Diabetic nephropathy is one of the most frequent, devastating and costly complications of diabetes. The available therapeutic approaches are limited. Dipeptidyl peptidase type 4 (DPP-4) inhibitors represent a new class of glucose-lowering drugs that might also have reno-protective properties. DPP-4 exists in two forms: a plasma membranebound form and a soluble form, and can exert many biological actions mainly through its peptidase activity and interaction with extracellular matrix components. The kidneys have the highest DPP-4 expression level in mammalians. DPP-4 expression and urinary activity are up-regulated in diabetic nephropathy, highlighting its role as a potential target to manage diabetic nephropathy. Preclinical animal studies and some clinical data suggest that DPP-4 inhibitors decrease the progression of diabetic nephropathy in a blood pressure-and glucose-independent manner. Many studies reported that these reno-protective effects could be due to increased half-life of DPP-4 substrates such as glucagon-like peptide-1 (GLP-1) and stromal derived factor-1 alpha (SDF-1a). However, the underlying mechanisms are far from being completely understood and clearly need further investigations. KW - DPP-4 KW - diabetic nephropathy KW - DPP-4 inhibitors KW - GLP-1 and SDF-1a Y1 - 2017 U6 - https://doi.org/10.1530/JME-17-0005 SN - 0952-5041 SN - 1479-6813 VL - 59 SP - R1 EP - R10 PB - Bioscientifica LTD CY - Bristol ER - TY - JOUR A1 - Lu, Yong-Ping A1 - Reichetzeder, Christoph A1 - Prehn, Cornelia A1 - von Websky, Karoline A1 - Slowinski, Torsten A1 - Chen, You-Peng A1 - Yin, Liang-Hong A1 - Kleuser, Burkhard A1 - Yang, Xue-Song A1 - Adamski, Jerzy A1 - Hocher, Berthold T1 - Fetal serum metabolites are independently associated with Gestational diabetes mellitus JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - 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 KW - Gestational diabetes KW - Metabolomics KW - Phosphatidylcholine acyl-alkyl C 32:1 KW - Proline Y1 - 2018 U6 - https://doi.org/10.1159/000487119 SN - 1015-8987 SN - 1421-9778 VL - 45 IS - 2 SP - 625 EP - 638 PB - Karger CY - Basel ER - TY - JOUR A1 - Lu, Yong-Ping A1 - Reichetzeder, Christoph A1 - Prehn, Cornelia A1 - Yin, Liang-Hong A1 - Yun, Chen A1 - Zeng, Shufei A1 - Chu, Chang A1 - Adamski, Jerzy A1 - Hocher, Berthold T1 - Cord blood Lysophosphatidylcholine 16:1 is positively associated with birth weight JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - 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 KW - Metabolomics KW - Lysophosphatidylcholine KW - Birth Weight KW - DOHaD KW - Hypertension KW - Type 2 Diabetes Y1 - 2018 U6 - https://doi.org/10.1159/000487118 SN - 1015-8987 SN - 1421-9778 VL - 45 IS - 2 SP - 614 EP - 624 PB - Karger CY - Basel ER - TY - JOUR A1 - Wang, Guang A1 - Li, Pei-zhi A1 - Zhang, Shi-yao A1 - Zhong, Shan A1 - Chu, Chang A1 - Zeng, Shufei A1 - Yan, Yu A1 - Cheng, Xin A1 - Chuai, Manli A1 - Hocher, Berthold A1 - Yang, Xuesong T1 - Lipopolysaccharides (LPS) Induced Angiogenesis During Chicken Embryogenesis is Abolished by Combined ETA/ETB Receptor Blockade JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - 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. KW - Lipopolysaccharides (LPS) KW - Angiogenesis KW - Chicken chorioallantoic membrane (CAM) KW - Endothelin (ET) Y1 - 2018 U6 - https://doi.org/10.1159/000492547 SN - 1015-8987 SN - 1421-9778 VL - 48 IS - 5 SP - 2084 EP - 2090 PB - Karger CY - Basel ER - TY - GEN A1 - Hocher, Berthold A1 - Zeng, Shufei T1 - Need for better PTH assays for clinical research and patient treatment T2 - Clinical chemistry and laboratory medicine : journal of the Forum of the European Societies of Clinical Chemistry - the European Branch of the International Federation of Clinical Chemistry and Laboratory Medicine Y1 - 2017 U6 - https://doi.org/10.1515/cclm-2017-0617 SN - 1434-6621 SN - 1437-4331 VL - 56 IS - 2 SP - 183 EP - 185 PB - De Gruyter CY - Berlin ER - TY - JOUR A1 - Beaumont, Robin N. A1 - Warrington, Nicole M. A1 - Cavadino, Alana A1 - Tyrrell, Jessica A1 - Nodzenski, Michael A1 - Horikoshi, Momoko A1 - Geller, Frank A1 - Myhre, Ronny A1 - Richmond, Rebecca C. A1 - Paternoster, Lavinia A1 - Bradfield, Jonathan P. A1 - Kreiner-Moller, Eskil A1 - Huikari, Ville A1 - Metrustry, Sarah A1 - Lunetta, Kathryn L. A1 - Painter, Jodie N. A1 - Hottenga, Jouke-Jan A1 - Allard, Catherine A1 - Barton, Sheila J. A1 - Espinosa, Ana A1 - Marsh, Julie A. A1 - Potter, Catherine A1 - Zhang, Ge A1 - Ang, Wei A1 - Berry, Diane J. A1 - Bouchard, Luigi A1 - Das, Shikta A1 - Hakonarson, Hakon A1 - Heikkinen, Jani A1 - Helgeland, Oyvind A1 - Hocher, Berthold A1 - Hofman, Albert A1 - Inskip, Hazel M. A1 - Jones, Samuel E. A1 - Kogevinas, Manolis A1 - Lind, Penelope A. A1 - Marullo, Letizia A1 - Medland, Sarah E. A1 - Murray, Anna A1 - Murray, Jeffrey C. A1 - Njolstad, Pal R. A1 - Nohr, Ellen A. A1 - Reichetzeder, Christoph A1 - Ring, Susan M. A1 - Ruth, Katherine S. A1 - Santa-Marina, Loreto A1 - Scholtens, Denise M. A1 - Sebert, Sylvain A1 - Sengpiel, Verena A1 - Tuke, Marcus A. A1 - Vaudel, Marc A1 - Weedon, Michael N. A1 - Willemsen, Gonneke A1 - Wood, Andrew R. A1 - Yaghootkar, Hanieh A1 - Muglia, Louis J. A1 - Bartels, Meike A1 - Relton, Caroline L. A1 - Pennell, Craig E. A1 - Chatzi, Leda A1 - Estivill, Xavier A1 - Holloway, John W. A1 - Boomsma, Dorret I. A1 - Montgomery, Grant W. A1 - Murabito, Joanne M. A1 - Spector, Tim D. A1 - Power, Christine A1 - Jarvelin, Marjo-Ritta A1 - Bisgaard, Hans A1 - Grant, Struan F. A. A1 - Sorensen, Thorkild I. A. A1 - Jaddoe, Vincent W. A1 - Jacobsson, Bo A1 - Melbye, Mads A1 - McCarthy, Mark I. A1 - Hattersley, Andrew T. A1 - Hayes, M. Geoffrey A1 - Frayling, Timothy M. A1 - Hivert, Marie-France A1 - Felix, Janine F. A1 - Hypponen, Elina A1 - Lowe, William L. A1 - Evans, David M. A1 - Lawlor, Debbie A. A1 - Feenstra, Bjarke A1 - Freathy, Rachel M. T1 - 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 JF - Human molecular genetics N2 - 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. Y1 - 2018 U6 - https://doi.org/10.1093/hmg/ddx429 SN - 0964-6906 SN - 1460-2083 VL - 27 IS - 4 SP - 742 EP - 756 PB - Oxford Univ. Press CY - Oxford ER - TY - GEN A1 - Reichetzeder, Christoph A1 - Hocher, Berthold T1 - DPP4 inhibition prevents AKI T2 - Oncotarget KW - acute kidney injury KW - DPP-4 inhibitors KW - ischemia reperfusion injury KW - gliptins KW - Dipeptidyl peptidase IV Y1 - 2017 U6 - https://doi.org/10.18632/oncotarget.20212 SN - 1949-2553 VL - 8 SP - 64655 EP - 64656 PB - Impact Journals LLC CY - Orchard Park ER - TY - GEN A1 - Hocher, Berthold A1 - Zeng, Shufei T1 - Clear the fog around parathyroid hormone assays BT - what do iPTH assays really measure? T2 - Clinical journal of the American Society of Nephrology KW - Assays KW - Biological Assay KW - CKD KW - oxidative stress KW - PTH Y1 - 2018 U6 - https://doi.org/10.2215/CJN.01730218 SN - 1555-9041 SN - 1555-905X VL - 13 IS - 4 SP - 524 EP - 526 PB - American Society of Nephrology CY - Washington ER - TY - JOUR A1 - Chaykovska, Lyubov A1 - Heunisch, Fabian A1 - von Einem, Gina A1 - Hocher, Carl-Friedrich A1 - Tsuprykov, Oleg A1 - Pavkovic, Mira A1 - Sandner, Peter A1 - Kretschmer, Axel A1 - Chu, Chang A1 - Elitok, Saban A1 - Stasch, Johannes-Peter A1 - Hocher, Berthold T1 - Urinary cGMP predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus before exposure to contrast medium JF - PLoS one N2 - 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. Y1 - 2018 U6 - https://doi.org/10.1371/journal.pone.0195828 SN - 1932-6203 VL - 13 IS - 4 PB - PLoS CY - San Fransisco ER - TY - JOUR A1 - Bär, Ludmilla A1 - Feger, Martina A1 - Fajol, Abul A1 - Klotz, Lars-Oliver A1 - Zeng, Shufei A1 - Lang, Florian A1 - Hocher, Berthold A1 - Föller, Michael T1 - Insulin suppresses the production of fibroblast growth factor 23 (FGF23) JF - Proceedings of the National Academy of Sciences of the United States of America N2 - 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. KW - PI3K KW - PKB/Akt KW - Klotho KW - phosphate Y1 - 2018 U6 - https://doi.org/10.1073/pnas.1800160115 SN - 0027-8424 VL - 115 IS - 22 SP - 5804 EP - 5809 PB - National Acad. of Sciences CY - Washington ER - TY - JOUR A1 - Tsuprykov, Oleg A1 - Chen, Xin A1 - Hocher, Carl-Friedrich A1 - Skoblo, Roman A1 - Yin, Lianghong A1 - Hocher, Berthold T1 - Why should we measure free 25(OH) vitamin D? JF - The Journal of Steroid Biochemistry and Molecular Biology N2 - 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. KW - 1,25(OH)(2) vitamin D KW - Bioavailable vitamin D KW - Calculated free 25(OH) vitamin D KW - Free 25(OH) vitamin D KW - Free vitamin D KW - Directly measured free vitamin D KW - Genetic polymorphism KW - Total 25(OH) vitamin D KW - Vitamin D-binding protein Y1 - 2107 U6 - https://doi.org/10.1016/j.jsbmb.2017.11.014 SN - 0960-0760 VL - 180 SP - 87 EP - 104 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - von Websky, Karoline A1 - Hasan, Ahmed Abdallah Abdalrahman Mohamed A1 - Reichetzeder, Christoph A1 - Tsuprykov, Oleg A1 - Hocher, Berthold T1 - Impact of vitamin D on pregnancy-related disorders and on offspring outcome JF - The Journal of Steroid Biochemistry and Molecular Biology N2 - 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. KW - Vitamin D deficiency KW - Free vitamin D KW - Vitamin D binding protein KW - Epigenetics KW - DNA methylation KW - Single nucleotide polymorphism KW - Preeclampsia KW - Gestational diabetes mellitus KW - Small for gestational age KW - Long term health Y1 - 2018 U6 - https://doi.org/10.1016/j.jsbmb.2017.11.008 SN - 0960-0760 VL - 180 SP - 51 EP - 64 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Tsuprykov, Oleg A1 - Buse, Claudia A1 - Skoblo, Roman A1 - Haq, Afrozul A1 - Hocher, Berthold T1 - Reference intervals for measured and calculated free 25-hydroxyvitamin D in normal pregnancy JF - The Journal of Steroid Biochemistry and Molecular Biology N2 - 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. KW - Measured free 25-hydroxyvitamin D KW - Calculated free 25-hydroxyvitamin D KW - Vitamin D-binding protein KW - Pregnancy KW - Reference intervals Y1 - 2018 U6 - https://doi.org/10.1016/j.jsbmb.2018.03.005 SN - 0960-0760 VL - 181 SP - 80 EP - 87 PB - Elsevier CY - Oxford 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 - Li, Jian A1 - Lu, Yong-Ping A1 - Tsuprykov, Oleg A1 - Hasan, Ahmed Abdallah Abdalrahman Mohamed A1 - Reichetzeder, Christoph A1 - Tian, Mei A1 - Zhang, Xiao Li A1 - Zhang, Qin A1 - Sun, Guo-Ying A1 - Guo, Jingli A1 - Gaballa, Mohamed Mahmoud Salem Ahmed A1 - Peng, Xiao-Ning A1 - Lin, Ge A1 - Hocher, Berthold T1 - Folate treatment of pregnant rat dams abolishes metabolic effects in female offspring induced by a paternal pre-conception unhealthy diet JF - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) N2 - 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. KW - Glucose tolerance KW - High-fat-sucrose-salt diet KW - Maternal folate treatment KW - Paternal programming Y1 - 2018 U6 - https://doi.org/10.1007/s00125-018-4635-x SN - 0012-186X SN - 1432-0428 VL - 61 IS - 8 SP - 1862 EP - 1876 PB - Springer CY - New York ER - TY - JOUR A1 - Gao, Lin-rui A1 - Wang, Guang A1 - Zhang, Jing A1 - Li, Shuai A1 - Chuai, Manli A1 - Bao, Yongping A1 - Hocher, Berthold A1 - Yang, Xuesong T1 - High salt-induced excess reactive oxygen species production resulted in heart tube malformation during gastrulation JF - Journal of Cellular Physiology N2 - 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. KW - cardiac progenitor migration and differentiation KW - chick embryo KW - heart tube KW - high salt KW - reactive oxygen species Y1 - 2018 U6 - https://doi.org/10.1002/jcp.26528 SN - 0021-9541 SN - 1097-4652 VL - 233 IS - 9 SP - 7120 EP - 7133 PB - Wiley CY - Hoboken 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 - GEN A1 - Tammen, Harald A1 - Koemhoff, Martin A1 - Mark, Michael A1 - Hocher, Berthold A1 - Delic, Denis A1 - Hess, Rüdiger A1 - von Eynatten, Maximilian A1 - Klein, Thomas T1 - Linagliptin treatment is associated with improved cobalamin (vitamin B-12) storage in mice and potentially in humans T2 - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) Y1 - 2018 SN - 0012-186X SN - 1432-0428 VL - 61 SP - S252 EP - S253 PB - Springer CY - New York ER - TY - JOUR A1 - Tao, Ting A1 - Su, Qiongli A1 - Xu, Simeng A1 - Deng, Jun A1 - Zhou, Sichun A1 - Zhuang, Yu A1 - Huang, Yanjun A1 - He, Caimei A1 - He, Shanping A1 - Peng, Mei A1 - Hocher, Berthold A1 - Yang, Xiaoping T1 - Down-regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP-1c axis JF - Journal of cellular physiology N2 - 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. KW - bladder cancer cells KW - FASN KW - p-AKT KW - PKM2 KW - p-mTOR KW - SREBP-1c Y1 - 2018 U6 - https://doi.org/10.1002/jcp.27129 SN - 0021-9541 SN - 1097-4652 VL - 234 IS - 3 SP - 3088 EP - 3104 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Middeldorp, Christel M. A1 - Mahajan, Anubha A1 - Horikoshi, Momoko A1 - Robertson, Neil R. A1 - Beaumont, Robin N. A1 - Bradfield, Jonathan P. A1 - Bustamante, Mariona A1 - Cousminer, Diana L. A1 - Day, Felix R. A1 - De Silva, N. Maneka A1 - Guxens, Monica A1 - Mook-Kanamori, Dennis O. A1 - St Pourcain, Beate A1 - Warrington, Nicole M. A1 - Adair, Linda S. A1 - Ahlqvist, Emma A1 - Ahluwalia, Tarunveer Singh A1 - Almgren, Peter A1 - Ang, Wei A1 - Atalay, Mustafa A1 - Auvinen, Juha A1 - Bartels, Meike A1 - Beckmann, Jacques S. A1 - Bilbao, Jose Ramon A1 - Bond, Tom A1 - Borja, Judith B. A1 - Cavadino, Alana A1 - Charoen, Pimphen A1 - Chen, Zhanghua A1 - Coin, Lachlan A1 - Cooper, Cyrus A1 - Curtin, John A. A1 - Custovic, Adnan A1 - Das, Shikta A1 - Davies, Gareth E. A1 - Dedoussis, George V. A1 - Duijts, Liesbeth A1 - Eastwood, Peter R. A1 - Eliasen, Anders U. A1 - Elliott, Paul A1 - Eriksson, Johan G. A1 - Estivill, Xavier A1 - Fadista, Joao A1 - Fedko, Iryna O. A1 - Frayling, Timothy M. A1 - Gaillard, Romy A1 - Gauderman, W. James A1 - Geller, Frank A1 - Gilliland, Frank A1 - Gilsanz, Vincente A1 - Granell, Raquel A1 - Grarup, Niels A1 - Groop, Leif A1 - Hadley, Dexter A1 - Hakonarson, Hakon A1 - Hansen, Torben A1 - Hartman, Catharina A. A1 - Hattersley, Andrew T. A1 - Hayes, M. Geoffrey A1 - Hebebrand, Johannes A1 - Heinrich, Joachim A1 - Helgeland, Oyvind A1 - Henders, Anjali K. A1 - Henderson, John A1 - Henriksen, Tine B. A1 - Hirschhorn, Joel N. A1 - Hivert, Marie-France A1 - Hocher, Berthold A1 - Holloway, John W. A1 - Holt, Patrick A1 - Hottenga, Jouke-Jan A1 - Hypponen, Elina A1 - Iniguez, Carmen A1 - Johansson, Stefan A1 - Jugessur, Astanand A1 - Kahonen, Mika A1 - Kalkwarf, Heidi J. A1 - Kaprio, Jaakko A1 - Karhunen, Ville A1 - Kemp, John P. A1 - Kerkhof, Marjan A1 - Koppelman, Gerard H. A1 - Korner, Antje A1 - Kotecha, Sailesh A1 - Kreiner-Moller, Eskil A1 - Kulohoma, Benard A1 - Kumar, Ashish A1 - Kutalik, Zoltan A1 - Lahti, Jari A1 - Lappe, Joan M. A1 - Larsson, Henrik A1 - Lehtimaki, Terho A1 - Lewin, Alexandra M. A1 - Li, Jin A1 - Lichtenstein, Paul A1 - Lindgren, Cecilia M. A1 - Lindi, Virpi A1 - Linneberg, Allan A1 - Liu, Xueping A1 - Liu, Jun A1 - Lowe, William L. A1 - Lundstrom, Sebastian A1 - Lyytikainen, Leo-Pekka A1 - Ma, Ronald C. W. A1 - Mace, Aurelien A1 - Magi, Reedik A1 - Magnus, Per A1 - Mamun, Abdullah A. A1 - Mannikko, Minna A1 - Martin, Nicholas G. A1 - Mbarek, Hamdi A1 - McCarthy, Nina S. A1 - Medland, Sarah E. A1 - Melbye, Mads A1 - Melen, Erik A1 - Mohlke, Karen L. A1 - Monnereau, Claire A1 - Morgen, Camilla S. A1 - Morris, Andrew P. A1 - Murray, Jeffrey C. A1 - Myhre, Ronny A1 - Najman, Jackob M. A1 - Nivard, Michel G. A1 - Nohr, Ellen A. A1 - Nolte, Ilja M. A1 - Ntalla, Ioanna A1 - Oberfield, Sharon E. A1 - Oken, Emily A1 - Oldehinkel, Albertine J. A1 - Pahkala, Katja A1 - Palviainen, Teemu A1 - Panoutsopoulou, Kalliope A1 - Pedersen, Oluf A1 - Pennell, Craig E. A1 - Pershagen, Goran A1 - Pitkanen, Niina A1 - Plomin, Robert A1 - Power, Christine A1 - Prasad, Rashmi B. A1 - Prokopenko, Inga A1 - Pulkkinen, Lea A1 - Raikkonen, Katri A1 - Raitakari, Olli T. A1 - Reynolds, Rebecca M. A1 - Richmond, Rebecca C. A1 - Rivadeneira, Fernando A1 - Rodriguez, Alina A1 - Rose, Richard J. A1 - Salem, Rany A1 - Santa-Marina, Loreto A1 - Saw, Seang-Mei A1 - Schnurr, Theresia M. A1 - Scott, James G. A1 - Selzam, Saskia A1 - Shepherd, John A. A1 - Simpson, Angela A1 - Skotte, Line A1 - Sleiman, Patrick M. A. A1 - Snieder, Harold A1 - Sorensen, Thorkild I. A. A1 - Standl, Marie A1 - Steegers, Eric A. P. A1 - Strachan, David P. A1 - Straker, Leon A1 - Strandberg, Timo A1 - Taylor, Michelle A1 - Teo, Yik-Ying A1 - Thiering, Elisabeth A1 - Torrent, Maties A1 - Tyrrell, Jessica A1 - Uitterlinden, Andre G. A1 - van Beijsterveldt, Toos A1 - van der Most, Peter J. A1 - van Duijn, Cornelia M. A1 - Viikari, Jorma A1 - Vilor-Tejedor, Natalia A1 - Vogelezang, Suzanne A1 - Vonk, Judith M. A1 - Vrijkotte, Tanja G. M. A1 - Vuoksimaa, Eero A1 - Wang, Carol A. A1 - Watkins, William J. A1 - Wichmann, H-Erich A1 - Willemsen, Gonneke A1 - Williams, Gail M. A1 - Wilson, James F. A1 - Wray, Naomi R. A1 - Xu, Shujing A1 - Xu, Cheng-Jian A1 - Yaghootkar, Hanieh A1 - Yi, Lu A1 - Zafarmand, Mohammad Hadi A1 - Zeggini, Eleftheria A1 - Zemel, Babette S. A1 - Hinney, Anke A1 - Lakka, Timo A. A1 - Whitehouse, Andrew J. O. A1 - Sunyer, Jordi A1 - Widen, Elisabeth E. A1 - Feenstra, Bjarke A1 - Sebert, Sylvain A1 - Jacobsson, Bo A1 - Njolstad, Pal R. A1 - Stoltenberg, Camilla A1 - Smith, George Davey A1 - Lawlor, Debbie A. A1 - Paternoster, Lavinia A1 - Timpson, Nicholas J. A1 - Ong, Ken K. A1 - Bisgaard, Hans A1 - Bonnelykke, Klaus A1 - Jaddoe, Vincent W. V. A1 - Tiemeier, Henning A1 - Jarvelin, Marjo-Riitta A1 - Evans, David M. A1 - Perry, John R. B. A1 - Grant, Struan F. A. A1 - Boomsma, Dorret I. A1 - Freathy, Rachel M. A1 - McCarthy, Mark I. A1 - Felix, Janine F. T1 - The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia BT - design, results and future prospects JF - European journal of epidemiology N2 - 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. KW - Genetics KW - Consortium KW - Childhood traits and disorders KW - Longitudinal Y1 - 2019 U6 - https://doi.org/10.1007/s10654-019-00502-9 SN - 0393-2990 SN - 1573-7284 VL - 34 IS - 3 SP - 279 EP - 300 PB - Springer CY - Dordrecht ER - TY - JOUR A1 - Warrington, Nicole A1 - Beaumont, Robin A1 - Horikoshi, Momoko A1 - Day, Felix R. A1 - Helgeland, Øyvind A1 - Laurin, Charles A1 - Bacelis, Jonas A1 - Peng, Shouneng A1 - Hao, Ke A1 - Feenstra, Bjarke A1 - Wood, Andrew R. A1 - Mahajan, Anubha A1 - Tyrrell, Jessica A1 - Robertson, Neil R. A1 - Rayner, N. William A1 - Qiao, Zhen A1 - Moen, Gunn-Helen A1 - Vaudel, Marc A1 - Marsit, Carmen A1 - Chen, Jia A1 - Nodzenski, Michael A1 - Schnurr, Theresia M. A1 - Zafarmand, Mohammad Hadi A1 - Bradfield, Jonathan P. A1 - Grarup, Niels A1 - Kooijman, Marjolein N. A1 - Li-Gao, Ruifang A1 - Geller, Frank A1 - Ahluwalia, Tarunveer Singh A1 - Paternoster, Lavinia A1 - Rueedi, Rico A1 - Huikari, Ville A1 - Hottenga, Jouke-Jan A1 - Lyytikäinen, Leo-Pekka A1 - Cavadino, Alana A1 - Metrustry, Sarah A1 - Cousminer, Diana L. A1 - Wu, Ying A1 - Thiering, Elisabeth Paula A1 - Wang, Carol A. A1 - Have, Christian Theil A1 - Vilor-Tejedor, Natalia A1 - Joshi, Peter K. A1 - Painter, Jodie N. A1 - Ntalla, Ioanna A1 - Myhre, Ronny A1 - Pitkänen, Niina A1 - van Leeuwen, Elisabeth M. A1 - Joro, Raimo A1 - Lagou, Vasiliki A1 - Richmond, Rebecca C. A1 - Espinosa, Ana A1 - Barton, Sheila J. A1 - Inskip, Hazel M. A1 - Holloway, John W. A1 - Santa-Marina, Loreto A1 - Estivill, Xavier A1 - Ang, Wei A1 - Marsh, Julie A. A1 - Reichetzeder, Christoph A1 - Marullo, Letizia A1 - Hocher, Berthold A1 - Lunetta, Kathryn L. A1 - Murabito, Joanne M. A1 - Relton, Caroline L. A1 - Kogevinas, Manolis A1 - Chatzi, Leda A1 - Allard, Catherine A1 - Bouchard, Luigi A1 - Hivert, Marie-France A1 - Zhang, Ge A1 - Muglia, Louis J. A1 - Heikkinen, Jani A1 - Morgen, Camilla S. A1 - van Kampen, Antoine H. C. A1 - van Schaik, Barbera D. C. A1 - Mentch, Frank D. A1 - Langenberg, Claudia A1 - Scott, Robert A. A1 - Zhao, Jing Hua A1 - Hemani, Gibran A1 - Ring, Susan M. A1 - Bennett, Amanda J. A1 - Gaulton, Kyle J. A1 - Fernandez-Tajes, Juan A1 - van Zuydam, Natalie R. A1 - Medina-Gomez, Carolina A1 - de Haan, Hugoline G. A1 - Rosendaal, Frits R. A1 - Kutalik, Zoltán A1 - Marques-Vidal, Pedro A1 - Das, Shikta A1 - Willemsen, Gonneke A1 - Mbarek, Hamdi A1 - Müller-Nurasyid, Martina A1 - Standl, Marie A1 - Appel, Emil V. R. A1 - Fonvig, Cilius Esmann A1 - Trier, Caecilie A1 - van Beijsterveldt, Catharina E. M. A1 - Murcia, Mario A1 - Bustamante, Mariona A1 - Bonàs-Guarch, Sílvia A1 - Hougaard, David M. A1 - Mercader, Josep M. A1 - Linneberg, Allan A1 - Schraut, Katharina E. A1 - Lind, Penelope A. A1 - Medland, Sarah Elizabeth A1 - Shields, Beverley M. A1 - Knight, Bridget A. A1 - Chai, Jin-Fang A1 - Panoutsopoulou, Kalliope A1 - Bartels, Meike A1 - Sánchez, Friman A1 - Stokholm, Jakob A1 - Torrents, David A1 - Vinding, Rebecca K. A1 - Willems, Sara M. A1 - Atalay, Mustafa A1 - Chawes, Bo L. A1 - Kovacs, Peter A1 - Prokopenko, Inga A1 - Tuke, Marcus A. A1 - Yaghootkar, Hanieh A1 - Ruth, Katherine S. A1 - Jones, Samuel E. A1 - Loh, Po-Ru A1 - Murray, Anna A1 - Weedon, Michael N. A1 - Tönjes, Anke A1 - Stumvoll, Michael A1 - Michaelsen, Kim Fleischer A1 - Eloranta, Aino-Maija A1 - Lakka, Timo A. A1 - van Duijn, Cornelia M. A1 - Kiess, Wieland A1 - Koerner, Antje A1 - Niinikoski, Harri A1 - Pahkala, Katja A1 - Raitakari, Olli T. A1 - Jacobsson, Bo A1 - Zeggini, Eleftheria A1 - Dedoussis, George V. A1 - Teo, Yik-Ying A1 - Saw, Seang-Mei A1 - Montgomery, Grant W. A1 - Campbell, Harry A1 - Wilson, James F. A1 - Vrijkotte, Tanja G. M. A1 - Vrijheid, Martine A1 - de Geus, Eco J. C. N. A1 - Hayes, M. Geoffrey A1 - Kadarmideen, Haja N. A1 - Holm, Jens-Christian A1 - Beilin, Lawrence J. A1 - Pennell, Craig E. A1 - Heinrich, Joachim A1 - Adair, Linda S. A1 - Borja, Judith B. A1 - Mohlke, Karen L. A1 - Eriksson, Johan G. A1 - Widen, Elisabeth E. A1 - Hattersley, Andrew T. A1 - Spector, Tim D. A1 - Kaehoenen, Mika A1 - Viikari, Jorma S. A1 - Lehtimaeki, Terho A1 - Boomsma, Dorret I. A1 - Sebert, Sylvain A1 - Vollenweider, Peter A1 - Sorensen, Thorkild I. A. A1 - Bisgaard, Hans A1 - Bonnelykke, Klaus A1 - Murray, Jeffrey C. A1 - Melbye, Mads A1 - Nohr, Ellen A. A1 - Mook-Kanamori, Dennis O. A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - Felix, Janine F. A1 - Jaddoe, Vincent W. V. A1 - Hansen, Torben A1 - Pisinger, Charlotta A1 - Vaag, Allan A. A1 - Pedersen, Oluf A1 - Uitterlinden, Andre G. A1 - Jarvelin, Marjo-Riitta A1 - Power, Christine A1 - Hypponen, Elina A1 - Scholtens, Denise M. A1 - Lowe, William L. A1 - Smith, George Davey A1 - Timpson, Nicholas J. A1 - Morris, Andrew P. A1 - Wareham, Nicholas J. A1 - Hakonarson, Hakon A1 - Grant, Struan F. A. A1 - Frayling, Timothy M. A1 - Lawlor, Debbie A. A1 - Njolstad, Pal R. A1 - Johansson, Stefan A1 - Ong, Ken K. A1 - McCarthy, Mark I. A1 - Perry, John R. B. A1 - Evans, David M. A1 - Freathy, Rachel M. T1 - Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors JF - Nature genetics N2 - 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. Y1 - 2019 SN - 1061-4036 SN - 1546-1718 VL - 51 IS - 5 SP - 804 EP - + PB - Nature Publ. Group CY - New York ER - TY - JOUR A1 - Groop, Per-Henrik A1 - Cooper, Mark E. A1 - Perkovic, Vlado A1 - Hocher, Berthold A1 - Kanasaki, Keizo A1 - Haneda, Masakazu A1 - Schernthaner, Guntram A1 - Sharma, Kumar A1 - Stanton, Robert C. A1 - Toto, Robert A1 - Cescutti, Jessica A1 - Gordat, Maud A1 - Meinicke, Thomas A1 - Koitka-Weber, Audrey A1 - Thiemann, Sandra A1 - von Eynatten, Maximilian T1 - Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction BT - the randomized MARLINA-T2D trial JF - Diabetes obesity & metabolism : a journal of pharmacology and therapeutics N2 - 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. KW - antidiabetic drug KW - clinical trial KW - diabetic nephropathy KW - DPP-IV inhibitor KW - glycaemic control KW - linagliptin Y1 - 2017 U6 - https://doi.org/10.1111/dom.13041 SN - 1462-8902 SN - 1463-1326 VL - 19 IS - 11 SP - 1610 EP - 1619 PB - Wiley CY - Hoboken ER - TY - GEN A1 - Hocher, Berthold A1 - Tsuprykov, Oleg T1 - Renoprotective effects of GLP1R agonists and SGLT2 inhibitors T2 - Nature reviews nephroloy N2 - New data from the LEADER trial show that the glucagon-like peptide 1 receptor agonist liraglutide protects against diabetic nephropathy in patients with type 2 diabetes mellitus. The renoprotective efficacy of liraglutide is not, however, as great as that reported for the sodium-glucose cotransporter 2 inhibitor emplagiflozin in the EMPA-REG OUTCOME trial. Y1 - 2017 U6 - https://doi.org/10.1038/nrneph.2017.140 SN - 1759-5061 SN - 1759-507X VL - 13 SP - 728 EP - 729 PB - Nature Publ. Group CY - New York ER - TY - JOUR A1 - Hasan, Ahmed Abdallah Abdalrahman Mohamed A1 - von Websky, Karoline A1 - Reichetzeder, Christoph A1 - Tsuprykov, Oleg A1 - Gaballa, Mohamed Mahmoud Salem Ahmed A1 - Guo, Jingli A1 - Zeng, Shufei A1 - Delic, Denis A1 - Tammen, Harald A1 - Klein, Thomas A1 - Kleuser, Burkhard A1 - Hocher, Berthold T1 - 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 JF - Kidney international : official journal of the International Society of Nephrology N2 - 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. KW - chronic kidney disease KW - collagen I KW - fibrosis KW - Glp1r(-/-) mice KW - HNRNPA1 KW - linagliptin KW - proteomic analysis KW - TGF-beta 1 KW - thymosin beta 4 KW - YB-1 Y1 - 2019 U6 - https://doi.org/10.1016/j.kint.2019.01.010 SN - 0085-2538 SN - 1523-1755 VL - 95 IS - 6 SP - 1373 EP - 1388 PB - Elsevier CY - New York ER - TY - JOUR A1 - Tian, Mei A1 - Reichetzeder, Christoph A1 - Li, Jian A1 - Hocher, Berthold T1 - Low birth weight, a risk factor for diseases in later life, is a surrogate of insulin resistance at birth JF - Journal of hypertension N2 - Low birth weight (LBW) is associated with diseases in adulthood. The birthweight attributed risk is independent of confounding such as gestational age, sex of the newborn but also social factors. The birthweight attributed risk for diseases in later life holds for the whole spectrum of birthweight. This raises the question what pathophysiological principle is actually behind the association. In this review, we provide evidence that LBW is a surrogate of insulin resistance. Insulin resistance has been identified as a key factor leading to type 2 diabetes, cardiovascular disease as well as kidney diseases. We first provide evidence linking LBW to insulin resistance during intrauterine life. This might be caused by both genetic (genetic variations of genes controlling glucose homeostasis) and/or environmental factors (due to alterations of macronutrition and micronutrition of the mother during pregnancy, but also effects of paternal nutrition prior to conception) leading via epigenetic modifications to early life insulin resistance and alterations of intrauterine growth, as insulin is a growth factor in early life. LBW is rather a surrogate of insulin resistance in early life - either due to inborn genetic or environmental reasons - rather than a player on its own. KW - epigenetics KW - fetal programing KW - genetics KW - insulin resistance KW - low birth weight Y1 - 2019 U6 - https://doi.org/10.1097/HJH.0000000000002156 SN - 0263-6352 SN - 1473-5598 VL - 37 IS - 11 SP - 2123 EP - 2134 PB - Kluwer CY - Philadelphia ER - TY - CHAP A1 - Tsuprykov, Oleg A1 - Buse, Claudia A1 - Skoblo, Roman A1 - Hocher, Berthold T1 - Free 25 (OH) vitamin D, but not total 25 (OH) vitamin D, is strongly correlated with gestational age and calcium in normal human pregnancy T2 - Journal of bone and mineral research Y1 - 2017 SN - 0884-0431 SN - 1523-4681 VL - 32 SP - S323 EP - S323 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Reichetzeder, Christoph A1 - von Websky, Karoline A1 - Tsuprykov, Oleg A1 - Samarin, Azadeh Mohagheghi A1 - Falke, Luise Gabriele A1 - Putra, Sulistyo Emantoko Dwi A1 - Hasan, Ahmed Abdallah Abdalrahman Mohamed A1 - Antonenko, Viktoriia A1 - Curato, Caterina A1 - Rippmann, Joerg A1 - Klein, Thomas A1 - Hocher, Berthold T1 - Head-to-head comparison of structurally unrelated dipeptidyl peptidase 4 inhibitors in the setting of renal ischemia reperfusion injury JF - British journal of pharmacology : journal of The British Pharmacological Society N2 - 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. Y1 - 2017 U6 - https://doi.org/10.1111/bph.13822 SN - 0007-1188 SN - 1476-5381 VL - 174 SP - 2273 EP - 2286 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Putra, Sulistyo E. Dwi A1 - Reichetzeder, Christoph A1 - Meixner, Martin A1 - Liere, Karsten A1 - Slowinski, Torsten A1 - Hocher, Berthold T1 - DNA methylation of the glucocorticoid receptor gene promoter in the placenta is associated with blood pressure regulation in human pregnancy JF - Journal of hypertension N2 - 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. KW - DNA methylation KW - epigenetics KW - glucocorticoid receptor KW - hypertension KW - hypotension KW - NR3C1 gene KW - placenta KW - pregnancy Y1 - 2017 U6 - https://doi.org/10.1097/HJH.0000000000001450 SN - 0263-6352 SN - 1473-5598 VL - 35 SP - 2276 EP - 2286 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Li, Jian A1 - Lu, Yong Ping A1 - Reichetzeder, Christoph A1 - Kalk, Philipp A1 - Kleuser, Burkhard A1 - Adamski, Jerzy A1 - Hocher, Berthold T1 - Maternal PCaaC38:6 is Associated With Preterm Birth - a Risk Factor for Early and Late Adverse Outcome of the Offspring JF - Journal of European public policy N2 - 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 KW - Metabolomics KW - PCaaC38:6 KW - Biomarker KW - Preterm birth Y1 - 2016 U6 - https://doi.org/10.1159/000443428 SN - 1420-4096 SN - 1423-0143 VL - 41 SP - 250 EP - 257 PB - Karger CY - Basel ER - TY - JOUR A1 - Hocher, Berthold A1 - Haumann, Hannah A1 - Rahnenführer, Jan A1 - Reichetzeder, Christoph A1 - Kalk, Philipp A1 - Pfab, Thiemo A1 - Tsuprykov, Oleg A1 - Winter, Stefan A1 - Hofmann, Ute A1 - Li, Jian A1 - Püschel, Gerhard Paul A1 - Lang, Florian A1 - Schuppan, Detlef A1 - Schwab, Matthias A1 - Schaeffeler, Elke T1 - Maternal eNOS deficiency determines a fatty liver phenotype of the offspring in a sex dependent manner JF - Epigenetics : the official journal of the DNA Methylation Society N2 - 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. KW - Epigenetics KW - eNOS KW - Fetal programming KW - fatty liver KW - metabolism Y1 - 2016 U6 - https://doi.org/10.1080/15592294.2016.1184800 SN - 1559-2294 SN - 1559-2308 VL - 11 SP - 539 EP - 552 PB - Routledge, Taylor & Francis Group CY - Philadelphia ER - TY - JOUR A1 - Reichetzeder, Christoph A1 - Putra, Sulistyo Emantoko Dwi A1 - Li, Jian A1 - Hocher, Berthold T1 - Developmental Origins of Disease - Crisis Precipitates Change JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - The concept of developmental origins of diseases has gained a huge interest in recent years and is a constantly emerging scientific field. First observations hereof originated from epidemiological studies, linking impaired birth outcomes to adult chronic, noncommunicable disease. By now there is a considerable amount of both epidemiological and experimental evidence highlighting the impact of early life events on later life disease susceptibility. Albeit far from being completely understood, more recent studies managed to elucidate underlying mechanisms, with epigenetics having become almost synonymous with developmental programming. The aim of this review was to give a comprehensive overview of various aspects and mechanisms of developmental origins of diseases. Starting from initial research foci mainly centered on a nutritionally impaired intrauterine environment, more recent findings such as postnatal nutrition, preterm birth, paternal programming and putative interventional approaches are summarized. The review outlines general underlying mechanisms and particularly discusses mechanistic explanations for sexual dimorphism in developmental programming. Furthermore, novel hypotheses are presented emphasizing a non-mendelian impact of parental genes on the offspring's phenotype. KW - Nutrition KW - Thrifty phenotype KW - Developmental programming KW - Paternal, maternal, sex differences KW - Epigenetics Y1 - 2016 U6 - https://doi.org/10.1159/000447801 SN - 1015-8987 SN - 1421-9778 VL - 39 SP - 919 EP - 938 PB - Karger CY - Basel ER - TY - JOUR A1 - Forssmann, Wolf-Georg A1 - Tillmann, Hanns-Christian A1 - Hock, Dieter A1 - Forssmann, Kristin A1 - Bernasconi, Corrado A1 - Forssmann, Ulf A1 - Richter, Rudolf A1 - Hocher, Berthold A1 - Pfuetzner, Andreas T1 - Pharmacokinetic and Pharmacodynamic Characteristics of Subcutaneously Applied PTH-1-37 JF - German politics N2 - 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 KW - Pharmacokinetics Y1 - 2016 U6 - https://doi.org/10.1159/000443453 SN - 1420-4096 SN - 1423-0143 VL - 41 SP - 507 EP - 518 PB - Karger CY - Basel ER - TY - JOUR A1 - Lu, Yong Ping A1 - Tsuprykov, Oleg A1 - Vignon-Zellweger, Nicolas A1 - Heiden, Susi A1 - Hocher, Berthold T1 - Global Overexpression of ET-1 Decreases Blood Pressure - A Systematic Review and Meta-Analysis of ET-1 Transgenic Mice JF - Naunyn-Schmiedeberg's archives of pharmacology N2 - 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 KW - Endothelin-1 transgenic mice KW - Blood pressure KW - Kidney weight KW - Heart weight Y1 - 2016 U6 - https://doi.org/10.1159/000450567 SN - 1420-4096 SN - 1423-0143 VL - 41 SP - 770 EP - 780 PB - Karger CY - Basel ER - TY - JOUR A1 - Chaykovska, Lyubov A1 - Heunisch, Fabian A1 - von Einem, Gina A1 - Alter, Markus L. A1 - Hocher, Carl-Friedrich A1 - Tsuprykov, Oleg A1 - Dschietzig, Thomas A1 - Kretschmer, Axel A1 - Hocher, Berthold T1 - Urinary Vitamin D Binding Protein and KIM-1 Are Potent New Biomarkers of Major Adverse Renal Events in Patients Undergoing Coronary Angiography JF - PLoS one N2 - 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. Y1 - 2016 U6 - https://doi.org/10.1371/journal.pone.0145723 SN - 1932-6203 VL - 11 PB - PLoS CY - San Fransisco ER - TY - JOUR A1 - Tsuprykov, Oleg A1 - Ando, Ryotaro A1 - Reichetzeder, Christoph A1 - von Websky, Karoline A1 - Antonenko, Viktoriia A1 - Sharkovska, Yuliya A1 - Chaykovska, Lyubov A1 - Rahnenfuehrer, Jan A1 - Hasan, Ahmed Abdallah Abdalrahman Mohamed A1 - Tammen, Harald A1 - Alter, Markus L. A1 - Klein, Thomas A1 - Ueda, Seiji A1 - Yamagishi, Sho-ichi A1 - Okuda, Seiya A1 - Hocher, Berthold T1 - The dipeptidyl peptidase inhibitor linagliptin and the angiotensin II receptor blocker telmisartan show renal benefit by different pathways in rats with 5/6 nephrectomy JF - Kidney international : official journal of the International Society of Nephrology N2 - 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/). KW - albuminuria KW - angiotensin receptor blockers KW - chronic kidney disease KW - DPP-4 inhibition KW - proteinuria KW - proteomic analysis Y1 - 2016 U6 - https://doi.org/10.1016/j.kint.2016.01.016 SN - 0085-2538 SN - 1523-1755 VL - 89 SP - 1049 EP - 1061 PB - Nature Publ. Group CY - New York ER - TY - JOUR A1 - Hecht, Eva A1 - Freise, Christian A1 - von Websky, Karoline A1 - Nasser, Hamoud A1 - Kretzschmar, Nadja A1 - Stawowy, Philipp A1 - Hocher, Berthold A1 - Querfeld, Uwe T1 - The matrix metalloproteinases 2 and 9 initiate uraemic vascular calcifications JF - Nephrology, dialysis, transplantation N2 - 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. KW - chronic kidney disease KW - matrix metalloproteinases KW - vascular calcification KW - vascular smooth muscle cells Y1 - 2016 U6 - https://doi.org/10.1093/ndt/gfv321 SN - 0931-0509 SN - 1460-2385 VL - 31 SP - 789 EP - 797 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Reichetzeder, Christoph A1 - Putra, S. E. Dwi A1 - Pfab, T. A1 - Slowinski, T. A1 - Neuber, Corinna A1 - Kleuser, Burkhard A1 - Hocher, Berthold T1 - Increased global placental DNA methylation levels are associated with gestational diabetes JF - Clinical epigenetics N2 - 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. KW - Placenta KW - Gestational diabetes KW - Insulin resistance KW - LC-MS/MS KW - Global DNA methylation KW - Epigenetics KW - Hypermethylation Y1 - 2016 U6 - https://doi.org/10.1186/s13148-016-0247-9 SN - 1868-7083 VL - 8 PB - BioMed Central CY - London ER - TY - GEN A1 - Schernthaner, G. A1 - Groop, P. A1 - Cooper, M. A1 - Perkovic, V A1 - Hocher, Berthold A1 - Kanasaki, K. A1 - Sharma, K. A1 - Stanton, R. A1 - Toto, R. A1 - Cescutti, Jessica A1 - Gordat, M. A1 - Meinicke, T. A1 - Koitka-Weber, A. A1 - Woerle, H. A1 - Eynatten, M. T1 - EFFECTS OF LINAGLIPTIN ON GLYCAEMIC CONTROL AND ALBUMINURIA IN TYPE 2 DIABETES - THE MARLINA-T2D (TM) TRIAL T2 - Nephrology Y1 - 2016 U6 - https://doi.org/10.1111/nep.12887 SN - 1320-5358 SN - 1440-1797 VL - 21 SP - 60 EP - 60 PB - Wiley-Blackwell CY - Hoboken ER - TY - JOUR A1 - Li, Jian A1 - Tsuprykov, Oleg A1 - Yang, Xiaoping A1 - Hocher, Berthold T1 - Paternal programming of offspring cardiometabolic diseases in later life JF - Journal of hypertension KW - cardiometabolic diseases KW - epigenetics KW - offspring KW - paternal programming KW - spermatogenesis KW - transgenerational effects Y1 - 2016 U6 - https://doi.org/10.1097/HJH.0000000000001051 SN - 0263-6352 SN - 1473-5598 VL - 34 SP - 2111 EP - 2126 PB - Wiley-Blackwell CY - Philadelphia 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 - GEN A1 - Lu, Yong-Ping A1 - Reichetzeder, Christoph A1 - Prehn, Cornelia A1 - von Websky, Karoline A1 - Slowinski, Torsten A1 - Chen, You-Peng A1 - Yin, Liang-Hong A1 - Kleuser, Burkhard A1 - Yang, Xue-Song A1 - Adamski, Jerzy A1 - Hocher, Berthold T1 - Fetal serum metabolites are independently associated with Gestational diabetes mellitus T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - 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 T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 637 KW - Gestational diabetes KW - metabolomics KW - phosphatidylcholine acyl-alkyl C 32:1 KW - proline Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-424585 SN - 1866-8372 IS - 637 ER - TY - GEN A1 - Beaumont, Robin N. A1 - Warrington, Nicole M. A1 - Cavadino, Alana A1 - Tyrrell, Jessica A1 - Nodzenski, Michael A1 - Horikoshi, Momoko A1 - Geller, Frank A1 - Myhre, Ronny A1 - Richmond, Rebecca C. A1 - Paternoster, Lavinia A1 - Bradfield, Jonathan P. A1 - Kreiner-Møller, Eskil A1 - Huikari, Ville A1 - Metrustry, Sarah A1 - Lunetta, Kathryn L. A1 - Painter, Jodie N. A1 - Hottenga, Jouke-Jan A1 - Allard, Catherine A1 - Barton, Sheila J. A1 - Espinosa, Ana A1 - Marsh, Julie A. A1 - Potter, Catherine A1 - Zhang, Ge A1 - Ang, Wei A1 - Berry, Diane J. A1 - Bouchard, Luigi A1 - Das, Shikta A1 - Hakonarson, Hakon A1 - Heikkinen, Jani A1 - Helgeland, Øyvind A1 - Hocher, Berthold A1 - Hofman, Albert A1 - Inskip, Hazel M. A1 - Jones, Samuel E. A1 - Kogevinas, Manolis A1 - Lind, Penelope A. A1 - Marullo, Letizia A1 - Medland, Sarah E. A1 - Murray, Anna A1 - Murray, Jeffrey C. A1 - Njølstad, Pa ̊l R. A1 - Nohr, Ellen A. A1 - Reichetzeder, Christoph A1 - Ring, Susan M. A1 - Ruth, Katherine S. A1 - Santa-Marina, Loreto A1 - Scholtens, Denise M. A1 - Sebert, Sylvain A1 - Sengpiel, Verena A1 - Tuke, Marcus A. A1 - Vaudel, Marc A1 - Weedon, Michael N. A1 - Willemsen, Gonneke A1 - Wood, Andrew R. A1 - Yaghootkar, Hanieh A1 - Muglia, Louis J. A1 - Bartels, Meike A1 - Relton, Caroline L. A1 - Pennell, Craig E. A1 - Chatzi, Leda A1 - Estivill, Xavier A1 - Holloway, John W. A1 - Boomsma, Dorret I. A1 - Montgomery, Grant W. A1 - Murabito, Joanne M. A1 - Spector, Tim D. A1 - Power, Christine A1 - Ja ̈rvelin, Marjo-Ritta A1 - Bisgaard, Hans A1 - Grant, Struan F.A. A1 - Sørensen, Thorkild I.A. A1 - Jaddoe, Vincent W. A1 - Jacobsson, Bo A1 - Melbye, Mads A1 - McCarthy, Mark I. A1 - Hattersley, Andrew T. A1 - Hayes, M. Geoffrey A1 - Frayling, Timothy M. A1 - Hivert, Marie-France A1 - Felix, Janine F. A1 - Hyppo ̈nen, Elina A1 - Lowe, William L. , Jr A1 - Evans, David M. A1 - Lawlor, Debbie A. A1 - Feenstra, Bjarke A1 - Freathy, Rachel M. T1 - 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 T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - 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 Â 10 À8 . 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. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 628 KW - alleles KW - birth weight KW - fetus KW - genotype KW - mothers KW - single nucleotide polymorphism KW - genetics KW - duration of gestation KW - genome-wide association study KW - offspring KW - biobanks Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-423100 SN - 1866-8372 IS - 628 ER - TY - GEN A1 - Lu, Yong-Ping A1 - Reichetzeder, Christoph A1 - Prehn, Cornelia A1 - Yin, Liang-Hong A1 - Yun, Chen A1 - Zeng, Shufei A1 - Chu, Chang A1 - Adamski, Jerzy A1 - Hocher, Berthold T1 - Cord blood Lysophosphatidylcholine 16:1 is positively associated with birth weight T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - 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 T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 631 KW - metabolomics KW - Lysophosphatidylcholine KW - birth weight KW - DOHaD KW - hypertension KW - Type 2 Diabetes Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-424566 SN - 1866-8372 IS - 631 ER - TY - GEN A1 - Wang, Guang A1 - Li, Pei-zhi A1 - Zhang, Shi-yao A1 - Zhong, Shan A1 - Chu, Chang A1 - Zeng, Shufei A1 - Yan, Yu A1 - Cheng, Xin A1 - Chuai, Manli A1 - Hocher, Berthold A1 - Yang, Xuesong T1 - Lipopolysaccharides (LPS) Induced Angiogenesis During Chicken Embryogenesis is Abolished by Combined ETA/ETB Receptor Blockade T2 - Cellular Physiology and Biochemistry N2 - 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. (C) 2018 The Author(s) Published by S. Karger AG, Basel T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 615 KW - Lipopolysaccharides (LPS) KW - Angiogenesis KW - Chicken chorioallantoic membrane (CAM) KW - Endothelin (ET) Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-424552 SN - 1866-8372 IS - 615 ER - TY - GEN A1 - Chaykovska, Lyubov A1 - Heunisch, Fabian A1 - von Einem, Gina A1 - Alter, Markus L. A1 - Hocher, Carl-Friedrich A1 - Tsuprykov, Oleg A1 - Dschietzig, Thomas A1 - Kretschmer, Axel A1 - Hocher, Berthold T1 - Urinary vitamin D binding protein and KIM-1 are potent new biomarkers of major adverse renal events in patients undergoing coronary angiography T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - 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. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 558 KW - acute kidney injury KW - cardiac surgery KW - molecule-1 KIM-1 KW - early diagnosis KW - failure KW - intervention KW - disease KW - NGAL Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-411928 SN - 1866-8372 IS - 558 ER - TY - GEN A1 - Hoffmann, Linda Sarah A1 - Kretschmer, Axel A1 - Lawrenz, Bettina A1 - Hocher, Berthold A1 - Stasch, Johannes-Peter T1 - Chronic activation of heme free Guanylate Cyclase leads to renal protection in Dahl salt-sensitive rats T2 - Postprints der Universität Potsdam : Mathematisch naturwissenschaftliche Reihe N2 - The nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine monophasphate (cGMP)-signalling pathway is impaired under oxidative stress conditions due to oxidation and subsequent loss of the prosthetic sGC heme group as observed in particular in chronic renal failure. Thus, the pool of heme free sGC is increased under pathological conditions. sGC activators such as cinaciguat selectively activate the heme free form of sGC and target the disease associated enzyme. In this study, a therapeutic effect of long-term activation of heme free sGC by the sGC activator cinaciguat was investigated in an experimental model of salt-sensitive hypertension, a condition that is associated with increased oxidative stress, heme loss from sGC and development of chronic renal failure. For that purpose Dahl/ss rats, which develop severe hypertension upon high salt intake, were fed a high salt diet (8% NaCl) containing either placebo or cinaciguat for 21 weeks. Cinaciguat markedly improved survival and ameliorated the salt-induced increase in blood pressure upon treatment with cinaciguat compared to placebo. Renal function was significantly improved in the cinaciguat group compared to the placebo group as indicated by a significantly improved glomerular filtration rate and reduced urinary protein excretion. This was due to anti-fibrotic and antiinflammatory effects of the cinaciguat treatment. Taken together, this is the first study showing that long-term activation of heme free sGC leads to renal protection in an experimental model of hypertension and chronic kidney disease. These results underline the promising potential of cinaciguat to treat renal diseases by targeting the disease associated heme free form of sGC. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 489 KW - signal-transduction system KW - nitric-oxide KW - oxidative stress KW - independent activation KW - endothelial dysfunction KW - pulmonary-hypertension KW - cardiovascular-disease KW - therapeutic target KW - heart-failure KW - cyclic-GMP Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-408088 SN - 1866-8372 IS - 489 ER - TY - GEN A1 - Groop, Per-Henrik A1 - Cooper, Mark E. A1 - Perkovic, Vlado A1 - Sharma, Kumar A1 - Schernthaner, Guntram A1 - Haneda, Masakazu A1 - Hocher, Berthold A1 - Gordat, Maud A1 - Cescutti, Jessica A1 - Woerle, Hans-Juergen A1 - von Eynatten, Maximilian T1 - Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction BT - Rationale and design of the MARLINA–T2D TM trial T2 - Diabetes & vascular disease research N2 - 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. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 419 KW - Dipeptidyl peptidase-4 inhibition KW - linagliptin KW - type 2 diabetes KW - chronic kidney disease KW - glycaemic control KW - albuminuria Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-404460 ER - TY - GEN A1 - Hocher, Berthold A1 - Reichetzeder, Christoph A1 - Dwi Putra, Sulistyo Emantoko A1 - Slowinski, Torsten A1 - Neuber, Corinna A1 - Kleuser, Burkhard A1 - Pfab, Thiemo T1 - Increased global placental DNA methylation levels are associated with gestational diabetes N2 - 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. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 370 KW - Placenta KW - Gestational diabetes KW - Insulin resistance KW - LC-MS/MS KW - Global DNA methylation KW - Epigenetics KW - Hypermethylation Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-400914 ER - TY - GEN A1 - Hocher, Berthold A1 - Oberthür, Dominik A1 - Slowinski, Torsten A1 - Querfeld, Uwe A1 - Schaefer, Franz A1 - Doyon, Anke A1 - Tepel, Martin A1 - Roth, Heinz J. A1 - Grön, Hans J. A1 - Reichetzeder, Christoph A1 - Betzel, Christian A1 - Armbruster, Franz Paul T1 - 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 N2 - 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. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 343 KW - n-oxPTH KW - chronic renal failure KW - kidney transplantation KW - hemodialysis KW - oxidation KW - PTH KW - chronic renal failure in children Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-399980 ER - TY - JOUR A1 - Dschietzig, Thomas Bernd A1 - Krause-Relle, Katharina A1 - Hennequin, Maud A1 - von Websky, Karoline A1 - Rahnenfuhrer, Jan A1 - Ruppert, Jana A1 - Groena, Hans Juergen A1 - Armbruster, Franz Paul A1 - Bathgate, Ross A. D. A1 - Aschenbach, Joerg R. A1 - Forssmann, Wolf-Georg A1 - Hocher, Berthold T1 - Relaxin-2 does not Ameliorate Nephropathy in an experimental model of Type-1 Diabetes JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie N2 - 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. KW - Diabetic nephropathy KW - Diabetic cardiomyopathy KW - Fibrosis KW - Inflammation KW - Relaxin Y1 - 2015 U6 - https://doi.org/10.1159/000368484 SN - 1420-4096 SN - 1423-0143 VL - 40 IS - 1 SP - 77 EP - 88 PB - Karger CY - Basel 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 - JOUR A1 - Tsuprykov, Oleg A1 - Chaykovska, Lyubov A1 - Kretschmer, Axel A1 - Stasch, Johannes-Peter A1 - Pfab, Thiemo A1 - Krause-Relle, Katharina A1 - Reichetzeder, Christoph A1 - Kalk, Philipp A1 - Adamski, Jerzy A1 - Hocher, Berthold T1 - Endothelin-1 overexpression improves renal function in eNOS knockout mice JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - 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 KW - Chronic kidney disease KW - Endothelial nitric oxide synthase KW - Endothelin KW - Mice KW - Nitric oxide Y1 - 2015 U6 - https://doi.org/10.1159/000438516 SN - 1015-8987 SN - 1421-9778 VL - 37 IS - 4 SP - 1474 EP - 1490 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 - Ong, Albert C. M. A1 - von Websky, Karoline A1 - Hocher, Berthold T1 - Endothelin and Tubulointerstitial Renal Disease JF - Seminars in nephrology N2 - All components of the endothelin (ET) system are present in renal tubular cells. In this review, we summarize current knowledge about ET and the most common tubular diseases: acute kidney injury (AKI) and polycystic kidney disease. AKI originally was called acute tubular necrosis, pointing to the most prominent morphologic findings. Similarly, cysts in polycystic kidney disease, and especially in autosomal-dominant polycystic kidney disease, are of tubular origin. Preclinical studies have indicated that the ET system and particularly ETA receptors are involved in the pathogenesis of ischemia-reperfusion injury, although these findings have not been translated to clinical studies. The ET system also has been implicated in radiocontrast-dye-induced AKI, however, ET-receptor blockade in a large human study was not successful. The ET system is activated in sepsis models of AKI; the effectiveness of ET blocking agents in preclinical studies is variable depending on the model and the ET-receptor antagonist used. Numerous studies have shown that the ET system plays an important role in the complex pathophysiology associated with cyst formation and disease progression in polycystic kidney disease. However, results from selective targeting of ET-receptor subtypes in animal models of polycystic kidney disease have proved disappointing and do not support clinical trials. These studies have shown that a critical balance between ETA and ETB receptor action is necessary to maintain structure and function in the cystic kidney. In summary, ETs have been implicated in the pathogenesis of several renal tubulointerstitial diseases, however, experimental animal findings have not yet led to use of ET blockers in human beings. (C) 2015 Elsevier Inc. All rights reserved. KW - Endothelin KW - acute kidney injury KW - polycystic kidney disease KW - ADPKD KW - ET-1 KW - ETA KW - ETB Y1 - 2015 U6 - https://doi.org/10.1016/j.semnephrol.2015.03.004 SN - 0270-9295 SN - 1558-4488 VL - 35 IS - 2 SP - 197 EP - 207 PB - Elsevier CY - Philadelphia ER - TY - CHAP A1 - Chen, Hong A1 - Reichetzeder, Christoph A1 - Föller, Michael A1 - Slowinski, Torsten A1 - Li, Jian A1 - Chen, You-Peng A1 - Lang, Florian A1 - Hocher, Berthold T1 - Maternal vitamin D deficiency and fetal programming T2 - Acta physiologica : official journal of the Federation of European Physiological Societies Y1 - 2015 SN - 1748-1708 SN - 1748-1716 VL - 213 SP - 155 EP - 156 PB - Wiley-Blackwell CY - Hoboken ER - TY - JOUR A1 - Stasch, Johannes-Peter A1 - Schlossmann, Jens A1 - Hocher, Berthold T1 - Renal effects of soluble guanylate cyclase stimulators and activators: A review of the preclinical evidence JF - Current opinion in pharmacology N2 - 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. Y1 - 2015 U6 - https://doi.org/10.1016/j.coph.2014.12.014 SN - 1471-4892 SN - 1471-4973 VL - 21 SP - 95 EP - 104 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Zirafi, Onofrio A1 - Kim, Kyeong-Ae A1 - Ständker, Ludger A1 - Mohr, Katharina B. A1 - Sauter, Daniel A1 - Heigele, Anke A1 - Kluge, Silvia F. A1 - Wiercinska, Eliza A1 - Chudziak, Doreen A1 - Richter, Rudolf A1 - Möpps, Barbara A1 - Gierschik, Peter A1 - Vas, Virag A1 - Geiger, Hartmut A1 - Lamla, Markus A1 - Weil, Tanja A1 - Burster, Timo A1 - Zgraja, Andreas A1 - Daubeuf, Francois A1 - Frossard, Nelly A1 - Hachet-Haas, Muriel A1 - Heunisch, Fabian A1 - Reichetzeder, Christoph A1 - Galzi, Jean-Luc A1 - Perez-Castells, Javier A1 - Canales-Mayordomo, Angeles A1 - Jimenez-Barbero, Jesus A1 - Gimenez-Gallego, Guillermo A1 - Schneider, Marion A1 - Shorter, James A1 - Telenti, Amalio A1 - Hocher, Berthold A1 - Forssmann, Wolf-Georg A1 - Bonig, Halvard A1 - Kirchhoff, Frank A1 - Münch, Jan T1 - Discovery and Characterization of an Endogenous CXCR4 Antagonist JF - Cell reports N2 - 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. Y1 - 2015 U6 - https://doi.org/10.1016/j.celrep.2015.03.061 SN - 2211-1247 VL - 11 IS - 5 SP - 737 EP - 747 PB - Cell Press CY - Cambridge ER - TY - CHAP A1 - Reichetzeder, Christoph A1 - von Websky, Karoline A1 - Tsuprykov, Oleg A1 - Antonenko, V. A1 - Samarin, Azin Mohagheghi A1 - Hocher, Berthold T1 - Effects of DPP-4 inhibition on glomerular and tubular function in a rat model of ischaemia-reperfusion injury T2 - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) Y1 - 2015 SN - 0012-186X SN - 1432-0428 VL - 58 SP - S34 EP - S35 PB - Springer CY - New York ER - TY - JOUR A1 - Satwiko, Muhammad Gahan A1 - Ikeda, Koji A1 - Nakayama, Kazuhiko A1 - Yagi, Keiko A1 - Hocher, Berthold A1 - Hirata, Ken-Ichi A1 - Emoto, Noriaki T1 - Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension JF - Biochemical and biophysical research communications N2 - 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. KW - Pulmonary arterial hypertension KW - Endothelin KW - Hypoxia KW - SU5416 Y1 - 2015 U6 - https://doi.org/10.1016/j.bbrc.2015.08.002 SN - 0006-291X SN - 1090-2104 VL - 465 IS - 3 SP - 356 EP - 362 PB - Elsevier CY - San Diego ER - TY - JOUR A1 - Groop, Per-Henrik A1 - Cooper, Mark E. A1 - Perkovic, Vlado A1 - Sharma, Kumar A1 - Schernthaner, Guntram A1 - Haneda, Masakazu A1 - Hocher, Berthold A1 - Gordat, Maud A1 - Cescutti, Jessica A1 - Woerle, Hans-Juergen A1 - von Eynatten, Maximilian T1 - 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 JF - Diabetes & vascular disease research : official journal of the International Society of Diabetes and Vascular Disease N2 - 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. KW - Dipeptidyl peptidase-4 inhibition KW - linagliptin KW - type 2 diabetes KW - chronic kidney disease KW - glycaemic control KW - albuminuria Y1 - 2015 U6 - https://doi.org/10.1177/1479164115579002 SN - 1479-1641 SN - 1752-8984 VL - 12 IS - 6 SP - 455 EP - 462 PB - Sage Publ. CY - London ER - TY - JOUR A1 - von Websky, Karoline A1 - Reichetzeder, Christoph A1 - Hocher, Berthold T1 - Physiology and pathophysiology of incretins in the kidney JF - Current opinion in nephrology and hypertension : reviews of all advances, evaluations of key references, comprehensive listing of papers N2 - Purpose of reviewIncretin-based therapy with glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors is considered a promising therapeutic option for type 2 diabetes mellitus. Cumulative evidence, mainly from preclinical animal studies, reveals that incretin-based therapies also may elicit beneficial effects on kidney function. This review gives an overview of the physiology, pathophysiology, and pharmacology of the renal incretin system.Recent findingsActivation of GLP-1R in the kidney leads to diuretic and natriuretic effects, possibly through direct actions on renal tubular cells and sodium transporters. Moreover, there is evidence that incretin-based therapy reduces albuminuria, glomerulosclerosis, oxidative stress, and fibrosis in the kidney, partially through GLP-1R-independent pathways. Molecular mechanisms by which incretins exert their renal effects are understood incompletely, thus further studies are needed.SummaryThe GLP-1R and DPP-4 are expressed in the kidney in various species. The kidney plays an important role in the excretion of incretin metabolites and most GLP-1R agonists and DPP-4 inhibitors, thus special attention is required when applying incretin-based therapy in renal impairment. Preclinical observations suggest direct renoprotective effects of incretin-based therapies in the setting of hypertension and other disorders of sodium retention, as well as in diabetic and nondiabetic nephropathy. Clinical studies are needed in order to confirm translational relevance from preclinical findings for treatment options of renal diseases. KW - DDP-4 inhibition KW - diabetes KW - diabetic nephropathy KW - GLP-1 receptor KW - hypertension KW - incretins KW - kidney KW - renal impairment Y1 - 2014 U6 - https://doi.org/10.1097/01.mnh.0000437542.77175.a0 SN - 1062-4821 SN - 1473-6543 VL - 23 IS - 1 SP - 54 EP - 60 PB - Lippincott Williams & Wilkins CY - Philadelphia 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 - Chaykovska, Lyubov A1 - Zientara, Alicja A1 - Reser, Diana A1 - Weise, Alexander A1 - Reichert, Wolfgang A1 - Hocher, Berthold T1 - Development and validation of a macroarray system - MutaCHIP (R) ARTERO - for the detection of genetic variants involved in the pathogenesis of atherosclerosis JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - 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. KW - cardiovascular disease KW - atherosclerosis KW - genes KW - rapid detection method KW - macroarray Y1 - 2014 U6 - https://doi.org/10.7754/Clin.Lab.2014.140104 SN - 1433-6510 VL - 60 IS - 5 SP - 873 EP - 878 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Lu, Yong-Ping A1 - Lung, Xu-Jing A1 - Xiao, Xiao-Min A1 - Huang, Si-Min A1 - Liu, Zhi-Wei A1 - Li, Jian A1 - Hocher, Berthold A1 - Chen, You-Peng T1 - Telbivudine during the second and third trimester of pregnancy interrupts HBV intrauterine transmission: a systematic review and meta-analysis JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - 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. KW - telbivudine KW - meta-analysis KW - intrauterine KW - transmission of hepatitis B virus (HBV) KW - clinical studies KW - safety efficacy Y1 - 2014 U6 - https://doi.org/10.7754/Clin.Lab.2013.130408 SN - 1433-6510 VL - 60 IS - 4 SP - 571 EP - 586 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Liang, Xu-Jing A1 - Huang, Si-Min A1 - Li, Jian-Ping A1 - Zhu, Xian-Nv A1 - Lu, Yong-Ping A1 - Hocher, Berthold A1 - Chen, You-Peng T1 - Hepatic impairment induced by scrub typhus is associated with new onset of renal dysfunction JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - 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. KW - hepatic impairment KW - renal dysfunction KW - complication KW - outcome KW - scrub typhus Y1 - 2014 U6 - https://doi.org/10.7754/Clin.Lab.2013.121203 SN - 1433-6510 VL - 60 IS - 1 SP - 63 EP - 68 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Chen, Yao A1 - Wang, Guang A1 - Wang, Xiao-yu A1 - Ma, Zheng-lai A1 - Chen, You-peng A1 - Chuai, Manli A1 - von Websky, Karoline A1 - Hocher, Berthold A1 - Yang, Xuesong T1 - Effects of high salt-exposure on the development of retina and lens in 5.5-Day Chick Embryo JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - 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. KW - Chick embryos KW - High osmolarity KW - Retina KW - Lens KW - Pax6 Y1 - 2014 U6 - https://doi.org/10.1159/000363044 SN - 1015-8987 SN - 1421-9778 VL - 34 IS - 3 SP - 804 EP - 817 PB - Karger CY - Basel ER - TY - JOUR A1 - Putra, Sulistyo Emantoko Dwi A1 - Tsuprykov, Oleg A1 - Von Websky, Karoline A1 - Ritter, Teresa A1 - Reichetzeder, Christoph A1 - Hocher, Berthold T1 - Dealing with large sample sizes: comparison of a new one spot dot blot method to western blot JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - 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. KW - one dot two development signals (ODTDS) dot blot KW - western blot KW - protein quantification KW - large sample size studies KW - comparison Y1 - 2014 U6 - https://doi.org/10.7754/Clin.Lab.2014.140317 SN - 1433-6510 VL - 60 IS - 11 SP - 1871 EP - 1877 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Li, Jian A1 - Chen, You-Peng A1 - Dong, Yun-Peng A1 - Yu, Cal-Hong A1 - Lu, Yong-Ping A1 - Xiao, Xiao-Min A1 - Hocher, Berthold T1 - The impact of umbilical blood flow regulation on fetal development differs in diabetic and non-diabetic pregnancy JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie N2 - 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. KW - Umbilical artery Doppler KW - Blood flow resistance KW - Gestational diabetes mellitus KW - Fetal development Y1 - 2014 U6 - https://doi.org/10.1159/000355815 SN - 1420-4096 SN - 1423-0143 VL - 39 IS - 4 SP - 369 EP - 377 PB - Karger CY - Basel ER - TY - JOUR A1 - Reichetzeder, Christoph A1 - Chen, Hong A1 - Foeller, Michael A1 - Slowinski, Torsten A1 - Li, Jian A1 - Chen, You-Peng A1 - Lang, Florian A1 - Hocher, Berthold T1 - Maternal vitamin D deficiency and fetal programming - lessons learned from humans and mice JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie N2 - 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. KW - Vitamin D KW - Birth weight KW - Preterm delivery KW - Fetal programming KW - Glucose tolerance KW - Cardiovascular diseases Y1 - 2014 U6 - https://doi.org/10.1159/000355809 SN - 1420-4096 SN - 1423-0143 VL - 39 IS - 4 SP - 315 EP - 329 PB - Karger CY - Basel ER - TY - CHAP A1 - Scholze, Alexandra A1 - Petersen, Lise A1 - Hocher, Berthold A1 - Rasmussen, Lars M. A1 - Tepel, Martin T1 - Role of fibroblast growth factor-23 and soluble alpha klotho in chronic kidney disease T2 - Nephrology, dialysis, transplantation Y1 - 2014 SN - 0931-0509 SN - 1460-2385 VL - 29 SP - 120 EP - 121 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Scholze, Alexandra A1 - Liu, Ying A1 - Pedersen, Lise A1 - Xia, Shengqiang A1 - Roth, Heinz J. A1 - Hocher, Berthold A1 - Rasmussen, Lars Melholt A1 - Tepel, Martin T1 - Soluble alpha-Klotho and its relation to kidney function and fibroblast growth factor-23 JF - The journal of clinical endocrinology & metabolism N2 - 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. Y1 - 2014 U6 - https://doi.org/10.1210/jc.2013-4171 SN - 0021-972X SN - 1945-7197 VL - 99 IS - 5 SP - E855 EP - E861 PB - Endocrine Society CY - Washington ER - TY - JOUR A1 - Chen, You-Peng A1 - Lu, Yong-Ping A1 - Li, Jian A1 - Liu, Zhi-Wei A1 - Chen, Wen-Jing A1 - Liang, Xu-Jing A1 - Chen, Xin A1 - Wen, Wang-Rong A1 - Xiao, Xiao-Min A1 - Reichetzeder, Christoph A1 - Hocher, Berthold T1 - Fetal and maternal angiotensin (1-7) are associated with preterm birth JF - Journal of hypertension N2 - 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. KW - angiotensin (1-7) KW - angiotensin II KW - cardiovascular disease KW - fetal programming KW - intrauterine fetal growth KW - pregnancy KW - preterm delivery Y1 - 2014 U6 - https://doi.org/10.1097/HJH.0000000000000251 SN - 0263-6352 SN - 1473-5598 VL - 32 IS - 9 SP - 1833 EP - 1841 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - CHAP A1 - Reichetzeder, Christoph A1 - Pasch, A. A1 - von Websky, Karoline A1 - Tsuprykov, Oleg A1 - Klein, T. A1 - Hocher, Berthold T1 - The DPP-4 inhibitor linagliptin increases plasma fetuin-A concentrations in a rat model of uraemic calcification T2 - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) Y1 - 2014 SN - 0012-186X SN - 1432-0428 VL - 57 SP - S522 EP - S522 PB - Springer CY - New York ER - TY - CHAP A1 - Hocher, Berthold A1 - Reichetzeder, Christoph A1 - von Websky, Karoline A1 - Tsuprykov, Oleg A1 - Klein, T. T1 - Dipeptidyl peptidase-4 inhibition in a rat model of ischaemia-reperfusion injury may accelerate tubular regeneration but does not improve glomerular filtration rate T2 - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) Y1 - 2014 SN - 0012-186X SN - 1432-0428 VL - 57 SP - S538 EP - S538 PB - Springer CY - New York ER - TY - JOUR A1 - Hocher, Berthold T1 - More than genes: the advanced fetal programming hypothesis JF - Journal of reproductive immunology : the international journal for experimental and clinical reproductive immunobiology N2 - 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. KW - Fetal programming KW - Advanced fetal programming hypothesis Y1 - 2014 U6 - https://doi.org/10.1016/j.jri.2014.03.001 SN - 0165-0378 VL - 104 SP - 8 EP - 11 PB - Elsevier CY - Clare 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 - 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 - Heunisch, Fabian A1 - von Einem, Gina A1 - Alter, Markus L. A1 - Weist, Andreas A1 - Dschietzig, Thomas A1 - Kretschmer, Axel A1 - Hocher, Berthold T1 - Urinary ET-1 excretion after exposure to radio-contrast media in diabetic patients and patients with preexisting mild impaired renal function JF - Life sciences : molecular, cellular and functional basis of therapy N2 - 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. KW - Urinary ET-1 KW - Clinical study KW - Radiocontrast media-induced nephropathy KW - Kidney Y1 - 2014 U6 - https://doi.org/10.1016/j.lfs.2013.12.233 SN - 0024-3205 SN - 1879-0631 VL - 118 IS - 2 SP - 440 EP - 445 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Vignon-Zellweger, Nicolas A1 - Relle, Katharina A1 - Rahnenfuehrer, Jan A1 - Schwab, Karima A1 - Hocher, Berthold A1 - Theuring, Franz T1 - Endothelin-1 overexpression and endothelial nitric oxide synthase knock-out induce different pathological responses in the heart of male and female mice JF - Life sciences : molecular, cellular and functional basis of therapy N2 - 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/). KW - Endothelin-1 KW - Nitric oxide KW - Cardiac function KW - Sexual dimorphism Y1 - 2014 U6 - https://doi.org/10.1016/j.lfs.2013.12.003 SN - 0024-3205 SN - 1879-0631 VL - 118 IS - 2 SP - 219 EP - 225 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Reichetzeder, Christoph A1 - Tsuprykov, Oleg A1 - Hocher, Berthold T1 - Endothelin receptor antagonists in clinical research - Lessons learned from preclinical and clinical kidney studies JF - Life sciences : molecular, cellular and functional basis of therapy N2 - Endothelin receptor antagonists (ETRAs) are approved for the treatment of pulmonary hypertension and scleroderma-related digital ulcers. The efforts to approve this class of drugs for renal indications, however, failed so far. Preclinical studies were promising. Transgenic overexpression of ET-1 or ET-2 in rodents causes chronic renal failure. Blocking the ET system was effective in the treatment of renal failure in rodent models. However, various animal studies indicate that blocking the renal tubular ETAR and ETBR causes water and salt retention partially mediated via the epithelial sodium transporter in tubular cells. ETRAs were successfully tested clinically in renal indications in phase 2 trials for the treatment of diabetic nephropathy. They showed efficacy in terms of reducing albumin excretion on top of guideline based background therapy (RAS blockade). However, these promising results could not be translated to successful phase Ill trials so far. The spectrum of serious adverse events was similar to other phase III trials using ETRAs. Potential underlying reasons for these failures and options to solve these issues are discussed. In addition preclinical and clinical studies suggest caution when addressing renal patient populations such as patients with hepatorenal syndrome, patients with any type of cystic kidney disease and patients at risk of contrast media induced nephropathy. The lessons learned in renal indications are also important for other potential promising indications of ETRAs like cancer and heart failure. (C) 2014 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/). KW - Endothelin receptor antagonists KW - Kidney KW - Side effects KW - Safety KW - Water and salt retention KW - Clinical trials Y1 - 2014 U6 - https://doi.org/10.1016/j.lfs.2014.02.025 SN - 0024-3205 SN - 1879-0631 VL - 118 IS - 2 SP - 141 EP - 148 PB - Elsevier CY - Oxford 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 - Kalk, Philipp A1 - von Websky, Karoline A1 - Relle, Katharina A1 - Pfab, Thiemo A1 - Alter, Markus L. A1 - Fischer, Yvan A1 - Hocher, Berthold T1 - Renoprotective effects of combined endothelin-converting enzyme/neutral endopeptidase inhibitor SLV338 in acute and chronic experimental renal damage JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - 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. KW - Renal failure KW - endothelin-converting enzyme KW - neutral endopeptidase Y1 - 2011 SN - 1433-6510 VL - 57 IS - 7-8 SP - 507 EP - 515 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg 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 - CHAP A1 - Geschka, Sandra A1 - Kretschmer, A. A1 - Sharkovska, J. A1 - Evgenov, O. V. A1 - Lawrenz, Bettina A1 - Stasch, Johannes-Peter A1 - Hocher, Berthold T1 - Soluble guanylate cyclase stimulation prevents fibrotic tissue Remodelling and improves survival in salt-sensitive dahl rats T2 - Journal of vascular research Y1 - 2011 SN - 1018-1172 VL - 48 IS - 4 SP - 171 EP - 171 PB - Karger CY - Basel ER - 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 - Wengenmayer, Christina A1 - Krikov, Maxim A1 - Mueller, Susanne A1 - Lucht, Kristin A1 - Villringer, Arno A1 - Hocher, Berthold A1 - Unger, Thomas A1 - Thoene-Reineke, Christa T1 - Novel therapy approach in primary stroke prevention simultaneous inhibition of endothelin converting enzyme and neutral endopeptidase in spontaneously hypertensive, stroke-prone rats improves survival JF - Neurological research : a journal of progress in neurosurgery and neurosciences N2 - 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. KW - Endothelin KW - Hypertension KW - Natriuretic peptides KW - Stroke Y1 - 2011 U6 - https://doi.org/10.1179/016164111X12881719352534 SN - 0161-6412 VL - 33 IS - 2 SP - 201 EP - 207 PB - Routledge, Taylor & Francis Group CY - Leeds ER - TY - JOUR A1 - Schildroth, Janice A1 - Rettig-Zimmermann, Juliane A1 - Kalk, Philipp A1 - Steege, Andreas A1 - Faehling, Michael A1 - Sendeski, Mauricio A1 - Paliege, Alexander A1 - Lai, En Yin A1 - Bachmann, Sebastian A1 - Persson, Pontus B. A1 - Hocher, Berthold A1 - Patzak, Andreas T1 - Endothelin type A and B receptors in the control of afferent and efferent arterioles in mice JF - Nephrology, dialysis, transplantation N2 - 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. KW - endothelin KW - ETB receptor-deficient mouse KW - glomerular arterioles KW - renal haemodynamics Y1 - 2011 U6 - https://doi.org/10.1093/ndt/gfq534 SN - 0931-0509 VL - 26 IS - 3 SP - 779 EP - 789 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Hocher, Berthold A1 - Heiden, Susi A1 - von Websky, Karoline A1 - Arafat, Ayman M. A1 - Rahnenführer, Jan A1 - Alter, Markus L. A1 - Kalk, Philipp A1 - Ziegler, Dieter A1 - Fischer, Yvan A1 - Pfab, Thiemo T1 - Renal effects of the novel selective adenosine A(1) receptor blocker SLV329 in experimental liver cirrhosis in rats JF - PLoS one N2 - 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. Y1 - 2011 U6 - https://doi.org/10.1371/journal.pone.0017891 SN - 1932-6203 VL - 6 IS - 3 PB - PLoS CY - San Fransisco ER - TY - JOUR A1 - Kalk, Philipp A1 - Sharkovska, Yuliya A1 - Kashina, Elena A1 - von Websky, Karoline A1 - Relle, Katharina A1 - Pfab, Thiemo A1 - Alter, Markus L. A1 - Guillaume, Philippe A1 - Provost, Daniel A1 - Hoffmann, Katrin A1 - Fischer, Yvan A1 - Hocher, Berthold T1 - Endothelin-Converting Enzyme/Neutral Endopeptidase Inhibitor SLV338 Prevents Hypertensive Cardiac Remodeling in a Blood Pressure-Independent Manner JF - HYPERTENSION N2 - 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.) KW - renovascular hypertension KW - cardiac remodeling KW - endothelin-converting enzyme KW - neutral endopeptidase KW - TGF-beta 1 Y1 - 2011 U6 - https://doi.org/10.1161/HYPERTENSIONAHA.110.163972 SN - 0194-911X VL - 57 IS - 4 SP - 755 EP - 763 PB - LIPPINCOTT WILLIAMS & WILKINS CY - PHILADELPHIA ER - TY - JOUR A1 - Vignon-Zellweger, Nicolas A1 - Relle, Katharina A1 - Kienlen, Elodie A1 - Alter, Markus L. A1 - Seider, Patrick A1 - Sharkovska, Juliya A1 - Heiden, Susi A1 - Kalk, Philipp A1 - Schwab, Karima A1 - Albrecht-Kuepper, Barbara A1 - Theuring, Franz A1 - Stasch, Johannes-Peter A1 - Hocher, Berthold T1 - Endothelin-1 overexpression restores diastolic function in eNOS knockout mice JF - Journal of hypertension N2 - 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. KW - cardiovascular diseases KW - endothelin KW - nitric oxide Y1 - 2011 U6 - https://doi.org/10.1097/HJH.0b013e3283450770 SN - 0263-6352 SN - 1473-5598 VL - 29 IS - 5 SP - 961 EP - 970 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Hocher, Berthold A1 - Heiden, S. A1 - von Websky, Karoline A1 - Rahnenführer, Jörg A1 - Kalk, Philipp A1 - Pfab, T. T1 - Dual endothelin-converting enzyme/neutral endopeptidase blockade in rats with D-galactosamine-induced liver failure JF - European journal of medical research : official organ "Deutsche AIDS-Gesellschaft" N2 - 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. KW - endothelin KW - endothelin-converting enzyme KW - neutral endopeptidase KW - D-galactosamine KW - acute liver failure Y1 - 2011 SN - 0949-2321 VL - 16 IS - 6 SP - 275 EP - 279 PB - Med. Scientific Publ. Holzapfel CY - München ER - TY - JOUR A1 - Geschka, Sandra A1 - Kretschmer, Axel A1 - Sharkovska, Yuliya A1 - Evgenov, Oleg V. A1 - Lawrenz, Bettina A1 - Hucke, Andreas A1 - Hocher, Berthold A1 - Stasch, Johannes-Peter T1 - Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in salt-sensitive dahl rats JF - PLoS one N2 - 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. Y1 - 2011 U6 - https://doi.org/10.1371/journal.pone.0021853 SN - 1932-6203 VL - 6 IS - 7 PB - PLoS CY - San Fransisco ER - TY - JOUR A1 - Li, Jian A1 - Wang, Zi-Neng A1 - Schlemm, Ludwig A1 - Pfab, Thiemo A1 - Xiao, Xiao-Min A1 - Chen, You-Peng A1 - Hocher, Berthold T1 - Low birth weight and elevated head-to-abdominal circumference ratio are associated with elevated fetal glycated serum protein concentrations JF - Journal of hypertension N2 - 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. KW - disproportional intrauterine growth retardation KW - insulin resistance KW - low birth weight KW - ultrasound Y1 - 2011 U6 - https://doi.org/10.1097/HJH.0b013e328349a2e6 SN - 0263-6352 VL - 29 IS - 9 SP - 1712 EP - 1718 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - CHAP A1 - Pfab, T. A1 - Sharkovska, Yukiya A1 - Alter, Markus L. A1 - von Websky, Karoline A1 - Mark, M. A1 - Klein, T. A1 - Hocher, Berthold T1 - Effect of linagliptin on infarction size and cardiac function in rats after myocardial ischaemia reperfusion T2 - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) Y1 - 2011 SN - 0012-186X VL - 54 SP - S329 EP - S329 PB - Springer CY - New York ER - TY - JOUR A1 - Hocher, Berthold A1 - Schlemm, Ludwig A1 - Haumann, Hannah A1 - Li, Jian A1 - Rahnenführer, Jan A1 - Guthmann, Florian A1 - Bamberg, Christian A1 - Kalk, Philipp A1 - Pfab, Thiemo A1 - Chen, You-Peng T1 - Offspring sex determines the impact of the maternal ACE I/D polymorphism on maternal glycaemic control during the last weeks of pregnancy JF - Journal of the renin angiotensin aldosterone system N2 - 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. KW - ACE I/D polymorphism KW - pregnancy KW - fetal sex KW - pregnancy induced diabetes KW - total glycated hemoglobin KW - glycemic control during pregnancy Y1 - 2011 U6 - https://doi.org/10.1177/1470320310387843 SN - 1470-3203 VL - 12 IS - 3 SP - 254 EP - 261 PB - Sage Publ. CY - London ER - TY - JOUR A1 - Chaykovska, Lyubov A1 - von Websky, Karoline A1 - Rahnenführer, Jan A1 - Alter, Markus L. A1 - Heiden, Susi A1 - Fuchs, Holger A1 - Runge, Frank A1 - Klein, Thomas A1 - Hocher, Berthold T1 - Effects of DPP-4 Inhibitors on the Heart in a Rat Model of Uremic Cardiomyopathy JF - PLoS one N2 - 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. Y1 - 2011 U6 - https://doi.org/10.1371/journal.pone.0027861 SN - 1932-6203 VL - 6 IS - 11 PB - PLoS CY - San Fransisco ER - TY - JOUR A1 - Espe, Katharina M. A1 - Raila, Jens A1 - Henze, Andrea A1 - Krane, Vera A1 - Schweigert, Florian J. A1 - Hocher, Berthold A1 - Wanner, Christoph A1 - Drechsler, Christiane T1 - Impact of vitamin A on clinical outcomes in haemodialysis patients JF - Nephrology, dialysis, transplantation N2 - 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. KW - haemodialysis KW - mortality KW - retinol KW - retinol-binding protein 4 KW - sudden death Y1 - 2011 U6 - https://doi.org/10.1093/ndt/gfr171 SN - 0931-0509 VL - 26 IS - 12 SP - 4054 EP - U583 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Sun, Sheng-Yun A1 - Huang, Jin A1 - Meng, Min-Jie A1 - Lu, Jia-Hai A1 - Hocher, Berthold A1 - Liu, Kang-Li A1 - Yang, Qin-He A1 - Zhu, Xiao-Feng T1 - Improvement of lipid profile and reduction of body weight by Shan He Jian Fei Granules in high fat diet-induced obese rats JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - 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. KW - obesity KW - high-fat diet KW - Shan He Jian Fei Granules (SHJFG) KW - lipid KW - adiponectin KW - resistin KW - leptin Y1 - 2012 SN - 1433-6510 VL - 58 IS - 1-2 SP - 81 EP - 87 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - CHAP A1 - Espe, Katharina M. A1 - Raila, Jens A1 - Henze, Andrea A1 - Blouin, Katja A1 - Schneider, A. A1 - Schmiedeke, D. A1 - Krane, Vera A1 - Schweigert, Florian J. A1 - Hocher, Berthold A1 - Wanner, Christoph A1 - Drechsler, Christiane T1 - Low vitamin E plasma levels are associated with cerebrovascular events and mortality in hemodialysis patients T2 - Annals of nutrition & metabolism : journal of nutrition, metabolic diseases and dietetics ; an official journal of International Union of Nutritional Sciences (IUNS) Y1 - 2012 SN - 0250-6807 VL - 60 IS - 2 SP - 137 EP - 137 PB - Karger CY - Basel ER -