title: Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen.
abstract: Kidney fibrosis is the final common pathway of all progressive chronic kidney diseases, of which diabetic nephropathy is the leading cause. Endothelial-to-mesenchymal transition (EndMT) has emerged as one of the most important origins of matrix-producing fibroblasts. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been introduced into the market as antidiabetes drugs. Here, we found that the DPP-4 inhibitor linagliptin ameliorated kidney fibrosis in diabetic mice without altering the blood glucose levels associated with the inhibition of EndMT and the restoration of microRNA 29s. Streptozotocin-induced diabetic CD-1 mice exhibited kidney fibrosis and strong immunoreactivity for DPP-4 by 24 weeks after the onset of diabetes. At 20 weeks after the onset of diabetes, mice were treated with linagliptin for 4 weeks. Linagliptin-treated diabetic mice exhibited a suppression of DPP-4 activity/protein expression and an amelioration of kidney fibrosis associated with the inhibition of EndMT. The therapeutic effects of linagliptin on diabetic kidneys were associated with the suppression of profibrotic programs, as assessed by mRNA microarray analysis. We found that the induction of DPP-4 observed in diabetic kidneys may be associated with suppressed levels of microRNA 29s in diabetic mice; linagliptin restored microRNA 29s and suppressed DPP-4 protein levels. Using cultured endothelial cells, we found that linagliptin inhibited TGF-β2-induced EndMT, and such anti-EndMT effects of linagliptin were mediated through microRNA 29 induction. These results indicate the possible novel pleiotropic action of linagliptin to restore normal kidney function in diabetic patients with renal impairment.
authors.affiliation: Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, Japan kkanasak@kanazawa-med.ac.jp koya0516@kanazawa-med.ac.jp.
authors.forename: Keizo
authors.initials: K
authors.lastname: Kanasaki
authors.affiliation: Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Sen
authors.initials: S
authors.lastname: Shi
authors.affiliation: Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Kanasaki
authors.affiliation: Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Jianhua
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Ishigaki
authors.affiliation: Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Munehiro
authors.initials: M
authors.lastname: Kitada
authors.affiliation: Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Swayam Prakash
authors.initials: SP
authors.lastname: Srivastava
authors.affiliation: Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, Japan kkanasak@kanazawa-med.ac.jp koya0516@kanazawa-med.ac.jp.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D005355:Fibrosis / Q000188:drug therapy; D005786:Gene Expression Regulation; D058685:Genetic Pleiotropy; D007150:Immunohistochemistry; D000069476:Linagliptin; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D035683:MicroRNAs / Q000378:metabolism; D011687:Purines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D013311:Streptozocin
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin; D013311:Streptozocin