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 - CHAP A1 - Hocher, Berthold A1 - Tsuprykov, Oleg A1 - Alter, Markus L. A1 - von Websky, Karoline A1 - Chaykovska, Lyubov A1 - Antonenko, V. A1 - Rahnenführer, Jan A1 - Klein, T. A1 - Reichetzeder, Christoph T1 - Linagliptin and the angiotensin II receptor blocker telmisartan show comparable efficacy but different renoprotective pathways in rats with 5/6 nephrectomy T2 - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) Y1 - 2013 SN - 0012-186X SN - 1432-0428 VL - 56 IS - 15-16 SP - S66 EP - S66 PB - Springer CY - New York 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 - Vignon-Zellweger, Nicolas A1 - Rahnenführer, Jan A1 - Theuring, Franz A1 - Hocher, Berthold T1 - Analysis of cardiac and renal endothelin receptors by in situ hybridization in mice JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - Background: Endothelin-1 (ET-1) is a multifunctional peptide, which is implicated in the renal and cardiac physicology as well as in many pathologies of these systems. ET-1's actions take place after the activation of two receptors: ETA and ETB. The expression of these receptors may be modulated during the pathologic process. The analysis of the distribution and level of expression of the receptors in animal models is therefore crucial. Methods: We developed a protocol for non-radioactive in situ hybridization for the mRNA of the two endothelin receptors on paraffin-embedded tissue using digoxigenin-labeled RNA probes. Results: In heart and kidney, the staining was reliable and specific. In a mouse model for endothelin/nitric oxide imbalance, cardiac ETB expression was reduced. The distribution of the receptors was in accordance with the actual knowledge. Differences in cell specific expression are discussed. Conclusions: We developed a protocol for the in situ hybridization of the endothelin receptors in mice. Given that the endothelin system is implicated in the development of many diseases, we believe that this protocol may be useful for a number of future preclinical studies. KW - Endothelin-1 KW - endothelin receptors KW - in situ hybridization KW - mouse Y1 - 2012 U6 - https://doi.org/10.7754/Clin.Lab.2012.120216 SN - 1433-6510 VL - 58 IS - 9-10 SP - 939 EP - 949 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - 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 - 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 - 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 -