@article{TsuprykovAndoReichetzederetal.2016,
  author    = {Tsuprykov, Oleg and Ando, Ryotaro and Reichetzeder, Christoph and von Websky, Karoline and Antonenko, Viktoriia and Sharkovska, Yuliya and Chaykovska, Lyubov and Rahnenfuehrer, Jan and Hasan, Ahmed Abdallah Abdalrahman Mohamed and Tammen, Harald and Alter, Markus L. and Klein, Thomas and Ueda, Seiji and Yamagishi, Sho-ichi and Okuda, Seiya and Hocher, Berthold},
  title     = {The dipeptidyl peptidase inhibitor linagliptin and the angiotensin II receptor blocker telmisartan show renal benefit by different pathways in rats with 5/6 nephrectomy},
  series = {Kidney international : official journal of the International Society of Nephrology},
  volume    = {89},
  journal   = {Kidney international : official journal of the International Society of Nephrology},
  publisher = {Nature Publ. Group},
  address   = {New York},
  issn      = {0085-2538},
  doi       = {10.1016/j.kint.2016.01.016},
  pages     = {1049 -- 1061},
  year      = {2016},
  abstract  = {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/).},
  language  = {en}
}
@article{HechtFreisevonWebskyetal.2016,
  author    = {Hecht, Eva and Freise, Christian and von Websky, Karoline and Nasser, Hamoud and Kretzschmar, Nadja and Stawowy, Philipp and Hocher, Berthold and Querfeld, Uwe},
  title     = {The matrix metalloproteinases 2 and 9 initiate uraemic vascular calcifications},
  series = {Nephrology, dialysis, transplantation},
  volume    = {31},
  journal   = {Nephrology, dialysis, transplantation},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {0931-0509},
  doi       = {10.1093/ndt/gfv321},
  pages     = {789 -- 797},
  year      = {2016},
  abstract  = {The matrix metalloproteinases (MMP) MMP-2 and MMP-9 are physiological regulators of vascular remodelling. Their dysregulation could contribute to vascular calcification. We examined the role of the MMP-2 and MMP-9 in uraemic vascular calcification in vivo and in vitro. The impact of pharmacological MMP inhibition on the development of media calcifications was explored in an aggressive animal model of uraemic calcification. In addition, the selective effects of addition and inhibition, respectively, of MMP-2 and MMP-9 on calcium-/phosphate-induced calcifications were studied in a murine cell line of vascular smooth muscle cells (VSMCs). High-dose calcitriol treatment of uraemic rats given a high phosphate diet induced massive calcifications, apoptosis and increased gene expressions of MMP-2, MMP-9 and of osteogenic transcription factors and proteins in aortic VSMC. The MMP inhibitor doxycycline prevented the VSMC transdifferentiation to osteoblastic cells, suppressed transcription of mediators of matrix remodelling and almost completely blocked aortic calcifications while further increasing apoptosis. Similarly, specific inhibitors of either MMP-2 or -9, or of both gelatinases (Ro28-2653) and a selective knockdown of MMP-2/-9 mRNA expression blocked calcification of murine VSMC induced by calcification medium (CM). In contrast to MMP inhibition, recombinant MMP-2 or MMP-9 enhanced CM-induced calcifications and the secretion of gelatinases. These data indicate that both gelatinases provide essential signals for phenotypic VSMC conversion, matrix remodelling and the initiation of vascular calcification. Their inhibition seems a promising strategy in the prevention of vascular calcifications.},
  language  = {en}
}
@article{HasanvonWebskyReichetzederetal.2019,
  author    = {Hasan, Ahmed Abdallah Abdalrahman Mohamed and von Websky, Karoline and Reichetzeder, Christoph and Tsuprykov, Oleg and Gaballa, Mohamed Mahmoud Salem Ahmed and Guo, Jingli and Zeng, Shufei and Delic, Denis and Tammen, Harald and Klein, Thomas and Kleuser, Burkhard and Hocher, Berthold},
  title     = {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},
  series = {Kidney international : official journal of the International Society of Nephrology},
  volume    = {95},
  journal   = {Kidney international : official journal of the International Society of Nephrology},
  number    = {6},
  publisher = {Elsevier},
  address   = {New York},
  issn      = {0085-2538},
  doi       = {10.1016/j.kint.2019.01.010},
  pages     = {1373 -- 1388},
  year      = {2019},
  abstract  = {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.},
  language  = {en}
}
@article{GroopCooperPerkovicetal.2015,
  author    = {Groop, Per-Henrik and Cooper, Mark E. and Perkovic, Vlado and Sharma, Kumar and Schernthaner, Guntram and Haneda, Masakazu and Hocher, Berthold and Gordat, Maud and Cescutti, Jessica and Woerle, Hans-Juergen and von Eynatten, Maximilian},
  title     = {Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: Rationale and design of the MARLINA-T2D trial},
  series = {Diabetes \& vascular disease research : official journal of the International Society of Diabetes and Vascular Disease},
  volume    = {12},
  journal   = {Diabetes \& vascular disease research : official journal of the International Society of Diabetes and Vascular Disease},
  number    = {6},
  publisher = {Sage Publ.},
  address   = {London},
  issn      = {1479-1641},
  doi       = {10.1177/1479164115579002},
  pages     = {455 -- 462},
  year      = {2015},
  abstract  = {Efficacy, Safety \& Modification of Albuminuria in Type 2 Diabetes Subjects with Renal Disease with LINAgliptin (MARLINA-T2D), a multicentre, multinational, randomized, double-blind, placebo-controlled, parallel-group, phase 3b clinical trial, aims to further define the potential renal effects of dipeptidyl peptidase-4 inhibition beyond glycaemic control. A total of 350 eligible individuals with inadequately controlled type 2 diabetes and evidence of renal disease are planned to be randomized in a 1:1 ratio to receive either linagliptin 5mg or placebo in addition to their stable glucose-lowering background therapy for 24weeks. Two predefined main endpoints will be tested in a hierarchical manner: (1) change from baseline in glycated haemoglobin and (2) time-weighted average of percentage change from baseline in urinary albumin-to-creatinine ratio. Both endpoints are sufficiently powered to test for superiority versus placebo after 24weeks with =0.05. MARLINA-T2D is the first of its class to prospectively explore both the glucose- and albuminuria-lowering potential of a dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes and evidence of renal disease.},
  language  = {en}
}