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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 -