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.
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.
authors.affiliation: Institute of Nutritional Sciences, University of Potsdam, Potsdam, Germany; Center for Cardiovascular Research, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Oleg
authors.initials: O
authors.lastname: Tsuprykov
authors.affiliation: Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Ando
authors.affiliation: Institute of Nutritional Sciences, University of Potsdam, Potsdam, Germany; Center for Cardiovascular Research, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Reichetzeder
authors.affiliation: Institute of Nutritional Sciences, University of Potsdam, Potsdam, Germany; Center for Cardiovascular Research, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Karoline
authors.initials: K
authors.lastname: von Websky
authors.affiliation: Institute of Nutritional Sciences, University of Potsdam, Potsdam, Germany; Center for Cardiovascular Research, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Viktoriia
authors.initials: V
authors.lastname: Antonenko
authors.affiliation: Institute of Vegetative Anatomy, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Sharkovska
authors.affiliation: Department of Cardiovascular Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Lyubov
authors.initials: L
authors.lastname: Chaykovska
authors.affiliation: Institute of Nutritional Sciences, University of Potsdam, Potsdam, Germany; Center for Cardiovascular Research, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Rahnenführer
authors.affiliation: Institute of Nutritional Sciences, University of Potsdam, Potsdam, Germany.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Hasan
authors.affiliation: PXBioVisioN GmbH, Hannover, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Tammen
authors.affiliation: Center for Cardiovascular Research, Charité - Universitätsmedizin Berlin, Berlin, Germany; Department of Nephrology and Endocrinology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Alter
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klein
authors.affiliation: Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Ueda
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Sho-Ichi
authors.initials: SI
authors.lastname: Yamagishi
authors.affiliation: Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Seiya
authors.initials: S
authors.lastname: Okuda
authors.affiliation: Institute of Nutritional Sciences, University of Potsdam, Potsdam, Germany; Institute for Laboratory Medicine, IFLB, Berlin, Germany; Department of Basic Medicine, Medical college of Hunan Normal University, Changsha, China. Electronic address: hocher@uni-potsdam.de.
authors.forename: Berthold
authors.initials: B
authors.lastname: Hocher
mesh_terms: D000419:Albuminuria / Q000201:enzymology / Q000517:prevention & control; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002853:Chromatography, Liquid; D018819:Dipeptidyl Peptidase 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D000069476:Linagliptin / Q000494:pharmacology*; D008297:Male; D013058:Mass Spectrometry; D009392:Nephrectomy / Q000379:methods*; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D012084:Renin-Angiotensin System / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D000077333:Telmisartan; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D015415:Biomarkers; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000069476:Linagliptin; C000602659:DPP4 protein, rat; D018819:Dipeptidyl Peptidase 4; D000077333:Telmisartan
keywords: DPP-4 inhibition; albuminuria; angiotensin receptor blockers; chronic kidney disease; proteinuria; proteomic analysis