title: Linagliptin Ameliorates Methylglyoxal-Induced Peritoneal Fibrosis in Mice.
abstract: Recent studies have reported increases of methylglyoxal (MGO) in peritoneal dialysis patients, and that MGO-mediated inflammation plays an important role in the development of peritoneal fibrosis through production of transforming growth factor-β1 (TGF-β1). Linagliptin, a dipeptidyl peptidase-4 inhibitor, exerts anti-inflammatory effects independent of blood glucose levels. In this study, we examined whether linagliptin suppresses MGO-induced peritoneal fibrosis in mice. Male C57/BL6 mice were divided into three groups: control, MGO injection plus saline, and MGO injection plus linagliptin (n = 6 per group). Peritoneal fibrosis was induced by daily intraperitoneal injection of saline containing 40 mmol/L MGO for 21 days. Saline was administered intraperitoneally to the control group. Linagliptin (10 mg/kg) or saline were administrated by once-daily oral gavage from 3 weeks before starting MGO injections. Immunohistochemical staining revealed that linagliptin suppressed expression of α-smooth muscle actin and fibroblast-specific protein-1, deposition of type I and III collagen, and macrophage (F4/80) infiltration. Peritoneal equilibration testing showed improved peritoneal functions in mice treated with linagliptin. Peritoneal injection of MGO increased plasma levels of glucagon-like peptide-1 (GLP-1) in mice, and a further increase was observed in linagliptin-treated mice. Although MGO increased plasma glucose levels, linagliptin did not decrease plasma glucose levels. Moreover, linagliptin reduced the TGF-β1 concentration in the peritoneal fluid of MGO-treated mice. GLP-1 receptor (GLP-1R) was expressed in monocytes/macrophages and linagliptin suppressed GLP-1R expression in MGO-injected mice. These results suggest that oral administration of linagliptin ameliorates MGO-induced peritoneal fibrosis.
authors: Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
authors: Takuo
authors: T
authors: Nagai
authors: Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
authors: Shigehiro
authors: S
authors: Doi
authors: Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
authors: Ayumu
authors: A
authors: Nakashima
authors: Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
authors: Taisuke
authors: T
authors: Irifuku
authors: Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
authors: Kensuke
authors: K
authors: Sasaki
authors: Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
authors: Toshinori
authors: T
authors: Ueno
authors: Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
authors: Takao
authors: T
authors: Masaki
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D007274:Injections, Intraperitoneal; D000069476:Linagliptin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D056627:Peritoneal Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D011765:Pyruvaldehyde / Q000633:toxicity*
chemical_list: D015415:Biomarkers; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000069476:Linagliptin; D011765:Pyruvaldehyde; D052216:Glucagon-Like Peptide 1