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 - 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 - JOUR A1 - Yang, Xiaoping A1 - Darko, Kwame Oteng A1 - Huang, Yanjun A1 - He, Caimei A1 - Yang, Huansheng A1 - He, Shanping A1 - Li, Jianzhong A1 - Li, Jian A1 - Hocher, Berthold A1 - Yin, Yulong T1 - Resistant starch regulates gut microbiota BT - structure, biochemistry and cell signalling JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - Starch is one of the most popular nutritional sources for both human and animals. Due to the variation of its nutritional traits and biochemical specificities, starch has been classified into rapidly digestible, slowly digestible and resistant starch. Resistant starch has its own unique chemical structure, and various forms of resistant starch are commercially available. It has been found being a multiple-functional regulator for treating metabolic dysfunction. Different functions of resistant starch such as modulation of the gut microbiota, gut peptides, circulating growth factors, circulating inflammatory mediators have been characterized by animal studies and clinical trials. In this mini-review, recent remarkable progress in resistant starch on gut microbiota, particularly the effect of structure, biochemistry and cell signaling on nutrition has been summarized, with highlights on its regulatory effect on gut microbiota. KW - Resistant starch KW - Gut microbiota KW - Nutrition Y1 - 2017 U6 - https://doi.org/10.1159/000477386 SN - 1015-8987 SN - 1421-9778 VL - 42 IS - 1 SP - 306 EP - 318 PB - Karger CY - Basel 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 - Reichetzeder, Christoph A1 - Alter, Markus L. T1 - Renal and cardiac effects of DPP-4 inhibitors - from preclinical development to clinical research JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie N2 - Inhibitors of type 4 dipeptidyl peptidase (DDP-4) were developed and approved for the oral treatment of type 2 diabetes. Its mode of action is to inhibit the degradation of incretins, such as type 1 glucagon like peptide (GLP-1), and GIP. GLP-1 stimulates glucose-dependent insulin secretion from pancreatic beta-cells and suppresses glucagon release from alpha-cells, thereby improving glucose control. Besides its action on the pancreas type 1 glucagon like peptide has direct effects on the heart, vessels and kidney mainly via the type 1 glucagon like peptide receptor (GLP-1R). Moreover, there are substrates of DPP-4 beyond incretins that have proven renal and cardiovascular effects such as BNP/ANP, NPY, PYY or SDF-1 alpha. Preclinical evidence suggests that DPP-4 inhibitors may be effective in acute and chronic renal failure as well as in cardiac diseases like myocardial infarction and heart failure. Interestingly, large cardiovascular meta-analyses of combined Phase II/III clinical trials with DPP-4 inhibitors point all in the same direction: a potential reduction of cardiovascular events in patients treated with these agents. A pooled analysis of pivotal Phase III, placebo-controlled, registration studies of linagliptin further showed a significant reduction of urinary albumin excretion after 24 weeks of treatment. The observation suggests direct renoprotective effects of DPP-4 inhibition that may go beyond its glucose-lowering potential. Type 4 dipeptidyl peptidase inhibitors have been shown to be very well tolerated in general, but for those excreted via the kidney dose adjustments according to renal function are needed to avoid side effects. In conclusion, the direct cardiac and renal effects seen in preclinical studies as well as meta-analysis of clinical trials may offer additional potentials - beyond improvement of glycemic control - for this newer class of drugs, such as acute kidney failure, chronic kidney failure as well as acute myocardial infarction and heart failure. KW - DDP-4 inhibition KW - Diabetes KW - GLP-1 KW - Cardiovascular effects KW - Myocardial infarction KW - Kidney KW - Diabetic nephropathy KW - Acute renal failure Y1 - 2012 U6 - https://doi.org/10.1159/000339028 SN - 1420-4096 VL - 36 IS - 1 SP - 65 EP - 84 PB - Karger CY - Basel ER - TY - JOUR A1 - Chaykovska, Lyubov A1 - Tsuprykov, Oleg A1 - Hocher, Berthold T1 - Biomarkers for the prediction of mortality and morbidity in patients with renal replacement therapy JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - The mortality of end-stage renal disease (ESRD) patients on dialysis remains high despite great improvement of dialysis technologies in the past decades. These patients die due to infectious diseases (mainly sepsis), cardiovascular diseases such as myocardial infarction, heart failure, stroke, and, in particular, sudden cardiac death. End stage renal disease is a complex condition, where the failure of kidney function is accompanied by numerous metabolic changes affecting almost all organ systems of the human body. Many of the biomarker characteristics of the individually affected organ systems have been associated with adverse outcomes. These biomarkers are different in patients with ESRD compared to the general population in the prediction of morbidity and mortality. Biomarker research in this field should aim to identify patients at risk for the different disease entities. Traditional biomarkers such as CRP, BNP, and troponins as well as new biomarkers such as fetuin, CD 154, and relaxin were analyzed in patients on dialysis. We will include observational as well as prospective clinical trials in this review. Furthermore, we will also discuss proteomics biomarker studies. The article assess the potential diagnostic value of different biomarkers in daily clinical practice as well as their usefulness for clinical drug development in end stage renal disease patients. Y1 - 2011 SN - 1433-6510 VL - 57 IS - 7-8 SP - 455 EP - 467 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - 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 - 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 - 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 - 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 -