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 - 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 - 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 - 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 - Rokutan, Hirofumi A1 - Suckow, Christian A1 - von Hähling, Stephan A1 - Strassburg, Sabine A1 - Bockmeyer, Barbara A1 - Döhner, Wolfram A1 - Waller, Christiane A1 - Bauersachs, Johann A1 - von Websky, Karoline A1 - Hocher, Berthold A1 - Anker, Stefan D. A1 - Springer, Jochen T1 - Furosemide induces mortality in a rat model of chronic heart failure JF - International journal of cardiology N2 - Objectives: In an experimental heart failure model, we tested the hypothesis that furosemide causes excess mortality. Background: Post-hoc analysis of large clinical heart failure trails revealed that furosemide treatment might be associated with worsening of morbidity and even mortality in heart failure patients. Methods and results: Myocardial infarction was induced in 7 +/- 1 week old male Wistar rats by ligation of the left coronary artery. In study 1, animals were randomly assigned to treatment with furosemide (10 mg/kg/d via drinking water, n = 33) or placebo (n = 33) starting 18 days after surgery. In study 2, animals received furosemide from day 18 and were then randomized to ongoing treatment with either furosemide only (n = 38) or furosemide plus ACE-inhibitor Ramipril (1 mg/kg/d, n = 38) starting on day 42. In study 1 survival rate in the furosemide group was lower than in the placebo group (hazard ratio {HR} 3.39, 95% confidence interval {CI} 1.14 to 10.09, p = 0.028). The furosemide group had a lower body weight (-6%, p = 0.028) at the end of the study and a higher sclerosis index of the glomeruli (+9%, p=0.026) than the placebo group. Wet lung weight, infarct size, and cardiac function were similar between the groups. In study 2, the furosemide group had a higher mortality rate than the furosemide + ramipril group (HR 4.55, 95% CI 2.0 to 10.0, p = 0.0003). Conclusion: In our rat model of heart failure furosemide, provided at a standard dose, was associated with increased mortality. This increased mortality could be prevented by additional administration of an ACE-inhibitor. KW - Angiotensin converting enzyme inhibitor KW - Furosemide KW - Heart failure KW - Loop diuretics KW - Mortality Y1 - 2012 U6 - https://doi.org/10.1016/j.ijcard.2011.03.005 SN - 0167-5273 VL - 160 IS - 1 SP - 20 EP - 25 PB - Elsevier CY - Clare 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 - 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 - 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 - Prommer, Hans-Ulrich A1 - Maurer, Johannes A1 - von Websky, Karoline A1 - Freise, Christian A1 - Sommer, Kerstin A1 - Nasser, Hamoud A1 - Samapati, Rudi A1 - Reglin, Bettina A1 - Guimaraes, Pedro A1 - Pries, Axel Radlach A1 - Querfeld, Uwe T1 - Chronic kidney disease induces a systemic microangiopathy, tissue hypoxia and dysfunctional angiogenesis JF - Scientific reports N2 - Chronic kidney disease (CKD) is associated with excessive mortality from cardiovascular disease (CVD). Endothelial dysfunction, an early manifestation of CVD, is consistently observed in CKD patients and might be linked to structural defects of the microcirculation including microvascular rarefaction. However, patterns of microvascular rarefaction in CKD and their relation to functional deficits in perfusion and oxygen delivery are currently unknown. In this in-vivo microscopy study of the cremaster muscle microcirculation in BALB/c mice with moderate to severe uremia, we show in two experimental models (adenine feeding or subtotal nephrectomy), that serum urea levels associate incrementally with a distinct microangiopathy. Structural changes were characterized by a heterogeneous pattern of focal microvascular rarefaction with loss of coherent microvascular networks resulting in large avascular areas. Corresponding microvascular dysfunction was evident by significantly diminished blood flow velocity, vascular tone, and oxygen uptake. Microvascular rarefaction in the cremaster muscle paralleled rarefaction in the myocardium, which was accompanied by a decrease in transcription levels not only of the transcriptional regulator HIF-1 alpha, but also of its target genes Angpt-2, TIE-1 and TIE-2, Flkt-1 and MMP-9, indicating an impaired hypoxia-driven angiogenesis. Thus, experimental uremia in mice associates with systemic microvascular disease with rarefaction, tissue hypoxia and dysfunctional angiogenesis. Y1 - 2018 U6 - https://doi.org/10.1038/s41598-018-23663-1 SN - 2045-2322 VL - 8 PB - Nature Publ. Group CY - London 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 -