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 uninephrectomized male rats by renal artery clamping for 30 min. The sham group 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 (8 mg·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: 15 mg·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.

Cardio Metabolic Diseases Boehringer Ingelheim Pharma GmbH and Co KG Biberach Germany

Center for Cardiovascular Research Charité Universitätsmedizin Berlin Berlin Germany

German Rheumatism Research Center Berlin Germany Cluster of Excellence NeuroCure Charité Universitätsmedizin Berlin Berlin Germany

Institute of Nutritional Science University of Potsdam Nuthetal Germany Center for Cardiovascular Research Charité Universitätsmedizin Berlin Berlin Germany

Institute of Nutritional Science University of Potsdam Nuthetal Germany Center for Cardiovascular Research Charité Universitätsmedizin Berlin Berlin Germany Institut für Laboratoriumsmedizin Berlin Germany

Institute of Nutritional Science University of Potsdam Nuthetal Germany Department of Biochemistry Faculty of Pharmacy Zagazig University Zagazig Egypt

Institute of Nutritional Science University of Potsdam Nuthetal Germany Faculty of Biotechnology University of Surabaya Surabaya Indonesia

Institute of Nutritional Science University of Potsdam Nuthetal Germany Institut für Laboratoriumsmedizin Berlin Germany Department of Basic Medicine Medical College of Hunan Normal University Changsha China

Institute of Nutritional Science University of Potsdam Nuthetal Germany Institute of Aquaculture University of South Bohemia České Budějovice Czech Republic

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