Decorin regulates cell activation and fibrotic processes in human peritoneal mesothelial cells through inhibition of ERK phosphorylation

Abstract

BACKGROUND: Mesothelial cell dysfunction contributes to peritoneal fibrosis during long-term peritoneal dialysis (PD). We previously demonstrated that mesothelial cells synthesize abundant decorin, a dermatan sulfate proteoglycan with anti-fibrotic properties. In this study, we investigated the mechanisms through which decorin regulates fibrogenesis and epithelial-to-mesenchymal transition (EMT) in human peritoneal mesothelial cells (HPMC) in the setting of PD. METHODS: Growth arrested HPMC were stimulated with spent non-infected or infected PD fluid in the presence or absence of exogenous decorin (0-1000 ng/ml) for 24h. Cell morphology, expression of fibronectin and fibroblast specific protein-1, and ERK activation were assessed. The effect of decorin gene silencing on cell activation and fibrotic processes in HPMC was also investigated. RESULTS: Non-infected PDF induced EMT and cell detachment in HPMC. These changes were more marked in cells exposed to infected PD fluid. Pre-incubation of HPMC with decorin preserved HPMC morphology and inhibited PD fluid-induced EMT, accompanied by decreased fibronectin synthesis and increased E-cadherin expression. The effect of decorin was mediated through the suppression of ERK phosphorylation. Knockdown of decorin expression in HPMC resulted in increased expression of fibroblast specific protein-1, fibronectin and TGF-β1 in both control and PD fluid stimulated HPMC (P<0.01, for all), accompanied by decreased E-cadherin expression (P<0.01, for all). CONCLUSIONS: The data demonstrate that decorin regulates cell activation and fibrotic processes in HPMC during PD through modulation of the ERK signaling pathway.