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Linagliptin Ameliorates Methylglyoxal-Induced Peritoneal Fibrosis in Mice
Takuo Nagai1, Shigehiro Doi1, Ayumu Nakashima1
1Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
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.
Insights
Linagliptin, an anti-inflammatory drug, was found to reduce methylglyoxal-induced peritoneal fibrosis in mice by suppressing key fibrotic markers and improving peritoneal function. This suggests a potential therapeutic role for linagliptin in managing peritoneal fibrosis.
Area of Science:
- Nephrology
- Pharmacology
- Pathology
Background:
- Methylglyoxal (MGO) increases in peritoneal dialysis patients, contributing to peritoneal fibrosis via inflammation and transforming growth factor-β1 (TGF-β1) production.
- Linagliptin, a dipeptidyl peptidase-4 inhibitor, possesses anti-inflammatory properties independent of glycemic control.
Purpose of the Study:
- To investigate the efficacy of linagliptin in ameliorating methylglyoxal (MGO)-induced peritoneal fibrosis in a mouse model.
Main Methods:
- Male C57/BL6 mice received daily intraperitoneal injections of MGO (40 mmol/L) for 21 days to induce peritoneal fibrosis.
- Linagliptin (10 mg/kg) or saline was administered orally daily, starting 3 weeks prior to MGO injections.
- Immunohistochemistry, peritoneal equilibration testing, and biochemical analyses were performed.
Main Results:
- Linagliptin significantly suppressed MGO-induced increases in α-smooth muscle actin, fibroblast-specific protein-1, collagen deposition, and macrophage infiltration.
- Peritoneal function was improved in linagliptin-treated mice.
- Linagliptin reduced peritoneal TGF-β1 levels and modulated glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R) expression.
Conclusions:
- Oral linagliptin administration effectively ameliorates methylglyoxal-induced peritoneal fibrosis in mice.
- The protective effects may involve the modulation of TGF-β1 and the GLP-1/GLP-1R pathway.
- Linagliptin shows promise as a therapeutic agent for peritoneal fibrosis, irrespective of its effects on blood glucose.
