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 - Chaykovska, Lyubov A1 - Alter, Markus L. A1 - von Websky, Karoline A1 - Hohmann, Margarete A1 - Tsuprykov, Oleg A1 - Reichetzeder, Christoph A1 - Kutil, Barbara A1 - Kraft, Robin A1 - Klein, Thomas A1 - Hocher, Berthold T1 - Effects of telmisartan and linagliptin when used in combination on blood pressure and oxidative stress in rats with 2-kidney-1-clip hypertension JF - Journal of hypertension N2 - Objective:To investigate the effects of linagliptin alone and in combination with the angiotensin II receptor blocker (ARB), telmisartan on blood pressure (BP), kidney function, heart morphology and oxidative stress in rats with renovascular hypertension.Methods:Fifty-seven male Wistar rats underwent unilateral surgical stenosis of the renal artery [2-kidney-1-clip (2k1c) method]. Animals were randomly divided into four treatment groups (n=14-18 per group) receiving: telmisartan (10mg/kg per day in drinking water), linagliptin (89ppm in chow), combination (linagliptin 89ppm+telmisartan 10mg/kg per day) or placebo. An additional group of 12 rats underwent sham surgery. BP was measured one week after surgery. Hypertensive animals entered a 16-week dosing period. BP was measured 2, 4, 8, 12 and 16 weeks after the initiation of treatment. Blood and urine were tested for assessment of kidney function and oxidative stress 6, 10, 14 and 18 weeks after surgery. Blood and urine sampling and organ harvesting were finally performed.Results:Renal stenosis caused an increase in meanSD systolic BP as compared with the sham group (157.7 +/- 29.3 vs. 106.2 +/- 20.5mmHg, respectively; P<0.001). Telmisartan alone and in combination with linagliptin, normalized SBP (111.1 +/- 24.3mmHg and 100.4 +/- 13.9mmHg, respectively; P<0.001 vs. placebo). Telmisartan alone and in combination with linagliptin significantly prevented cardiac hypertrophy, measured by heart weight and myocyte diameter. Renal function measured by cystatin C was not affected by 2k1c surgery. Telmisartan significantly increased plasma concentration of cystatin C. 2k1c surgery initiated fibrosis in both kidneys. Telmisartan promoted further fibrotic changes in the clipped kidney, as measured by protein expression of Col1a1 and histology for interstitial fibrosis and glomerulosclerosis. In non-clipped kidneys, telmisartan demonstrated antifibrotic properties, reducing Col1a1 protein expression. Plasma levels of oxidized low-density lipoprotein were higher in the placebo-treated 2k1c rats as compared to sham-operated animals. The increase was abolished by linagliptin alone (P=0.03 vs. placebo) and in combination with telmisartan (P=0.02 vs. placebo). Combination therapy also significantly reduced plasma concentration of carbonyl proteins (P=0.04 vs. placebo).Conclusion:Inhibition of type 4 dipeptidyl peptidase with linagliptin did not counter BP-lowering effects of ARB in 2k1c rats. Linagliptin reduced lipid and protein oxidation in 2k1c rats, and this effect was BP-independent. KW - 2k1c renovascular hypertension KW - blood pressure KW - DPP4 inhibition KW - linagliptin KW - oxidative stress Y1 - 2013 U6 - https://doi.org/10.1097/HJH.0b013e3283649b4d SN - 0263-6352 SN - 1473-5598 VL - 31 IS - 11 SP - 2290 EP - 2299 PB - Lippincott Williams & Wilkins CY - Philadelphia 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 - 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 - 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 -