Anti-fibrotic Effect of Decorin in Peritoneal Dialysis

Abstract

Objectives: Progressive peritoneal fibrosis is a common complication in patients on long‐term peritoneal dialysis (PD), and PD‐associated peritonitis is an important exacerbating factor for peritoneal fibrosis. This study investigated the anti‐fibrotic effect of decorin on fibrogenesis in human peritoneal mesothelial cells (HPMC). Methods: Dialysate decorin level in stable PD patients and those with peritonitis was determined by ELISA. The effect of decorin on fibrotic processes was conducted in cultured HPMC. Results: Dialysate decorin level showed an inverse relationship with time on PD and was significantly lower compared with baseline after two years of PD (P < 0.05). Dialysate decorin level correlated with dialysate CA125 level. Peritonitis episodes were associated with a significant decrease in dialysate decorin, which persisted for more than 3 months despite clinical resolution of peritonitis. At the onset of peritonitis, dialysate decorin level correlated with that of TGF‐β1, and inversely correlated with IL‐1β. In cultured HPMC, exogenous TGF‐β1 and IL‐1β reduced decorin secretion and induced fibronectin expression, and these effects were mediated through increased p38 MAPK and AKT/PI3K phosphorylation. Almost all of the fibronectin expressed by HPMC, with or without exposure to PD fluid or pro‐fibrotic cytokines, was deposited in the extracellular matrix. Decorin abrogated HPMC fibronectin expression induced by PD fluid or pro‐fibrotic cytokines, mediated in part through decreased p38 MAPK and AKT/PI3K and increased GSK‐3β phosphorylation. Decorin gene silencing resulted in an increase in fibronectin expression. Conclusions: Our data provide evidence of the anti‐fibrotic effect of decorin in HPMC. Long‐term PD is associated with decreased dialysate decorin level, especially during episodes of peritonitis. The effect of adding decorin to peritoneal dialysate on peritoneal fibrosis warrants further investigation.