Decorin inhibits epithelial-to-mesenchymal transition and fibronectin synthesis in peritoneal mesothelial cells

Abstract

INTRODUCTION AND AIMS: Peritonitis is an important cause of peritoneal membrane failure in patients on peritoneal dialysis (PD). Decorin is a dermatan sulfate proteoglycan that possesses anti-fibrotic properties. Its role in peritoneal fibrosis remains to be fully defined. This study examined the relationship between dialysate levels of decorin and pro-inflammatory and fibrotic mediators in patients with PD associated peritonitis, and investigated the role of decorin in mesothelial cell fibrogenesis. METHODS: Serial aliquots (50ml) of PD fluid were collected from 43 patients with PD-related peritonitis. Dialysate samples from 20 PD patients who were peritonitis-free in the past 12 months were included as controls. Dialysate concentrations of decorin, TGF-β1, IL-1β, IL-6 and IL-8 were measured using commercially available ELISAs. Cultured mesothelial cells were incubated with spent PD fluid in the presence or absence of exogenous decorin, and the expression of SNAIL and fibronectin determined. RESULTS: Dialysate decorin level was significantly higher at the onset of peritonitis compared to non-peritonitis dialysate (6345.23±1169.38 vs 257.6±26.9 pg/ml, P<0.05). Decorin level peaked 3 days after the onset of peritonitis and its level at 3 months remained higher than that in non-peritonitis patients (8729.14±1145.21 pg/ml, P<0.05). Dialysate decorin level showed a positive correlation with TGF-β1 (r= 0.31, P<0.05), and an inverse correlation with dialysate IL-1β, IL-6 and IL-8 levels (r= -0.34, -0.38 and -0.32 respectively, P<0.05 for all). Spent PD fluid at the onset of peritonitis induced phenotypic changes in mesothelial cells with loss of epithelial morphology and the acquisition of fibroblastic features. This was accompanied by increased SNAIL and fibronectin synthesis. Exogenous decorin improved mesothelial cell morphology and decreased SNAIL and fibronectin synthesis, mediated in part though reduced p38 MAPK activation. CONCLUSIONS: Our data suggest a beneficial role for decorin in ameliorating peritonitis-mediated fibrotic processes in peritoneal mesothelial cells.