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.
Highlights
Peritoneal dialysis (PD) is a well-established renal replacement therapy for patients with endstage kidney disease
Linagliptin decreases the expression of α-smooth muscle actin (α-SMA) and fibroblast-specific protein-1 (FSP-1) in mice with MGO-induced peritoneal fibrosis
Linagliptin administration significantly reduced the α-SMA-positive area compared with that in the MGO + saline group (Fig 2C), and reduced the number of FSP-1-positive cells that had accumulated in the upper layer of the submesothelial compact zone (Fig 2B)
Summary
Peritoneal dialysis (PD) is a well-established renal replacement therapy for patients with endstage kidney disease. Long term exposure to PD fluid leads to inflammation and eventual peritoneal fibrosis that is clinically presented as the failure of peritoneal ultrafiltration [1,2,3,4,5]. Linagliptin Inhibits Peritoneal Fibrosis does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. As a major contributor to fibrosis, transforming growth factor-β1 (TGF-β1) from macrophages has been identified in the peritoneum as well as various other tissues [7,12,13,14]. Inhibition of TGF-β1 production has not yet been achieved in a clinical setting
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