Anti-fibrotic effect of decorin in peritoneal dialysis and PD-associated peritonitis

Abstract

Background: Progressive peritoneal fibrosis is a common complication in patients on long-term peritoneal dialysis (PD). PD-associated peritonitis is a major exacerbating factor. We investigated the anti-fibrotic properties of decorin secreted by peritoneal mesothelial cells. Methods: Dialysate decorin level in stable PD patients and those with peritonitis was measured. In vitro experiments were conducted to investigate the effect of decorin in fibrotic response in human peritoneal mesothelial cells (HPMC). Findings: Increasing PD duration was associated with a progressive decrease of dialysate decorin and CA125 levels. Dialysate decorin level correlated with CA125 level. Peritonitis episodes were associated with a massive drop of dialysate decorin, which persisted for over three months despite clinical recovery. Dialysate decorin level correlated with that of TGF-b1, but was inversely related to IL-1b and IL-8. TGF-b1, IL-1b, IL-6, IL-8, or TNF-a reduced decorin secretion in HPMC, but induced fibronectin expression. The effects were mediated in part through increased p38 MAPK and AKT/PI3K phosphorylation. Decorin abrogated the induction of fibronectin expression in mesothelial cells by PD fluids or pro-fibrotic cytokines, through decreased TGF-bRI, p38 MAPK and AKT/PI3K phosphorylation and increased glycogen synthase kinase-3b phosphorylation. Decorin gene-silencing resulted in increased fibronectin expression under these conditions. Interpretation: Our data demonstrate anti-fibrotic actions of decorin in HPMC, when these cells are subjected to the pro-fibrotic effect of peritoneal dialysate and pro-fibrotic cytokines in PD, especially during peritonitis.

Convergent genomic and pharmacological evidence of PI3K/GSK3 signaling alterations in neurons from schizophrenia patients

“…Among the top 5 DEGs were DCN, PRG4, OGN, ITGA8, and ASPN, all of which are involved in mediating cell–cell interactions, ECM formation, and cell migration. Importantly, ECM proteins are known to function via PI3K/GSK3 signaling, including ITGA8 [ 55 ], DCN [ 67 , 68 ], and OGN [ 69 ], identified as top DEG’s, and ITGA8 and collagen subunits [ 56 , 57 ] identified as part of the PI3K/GSK3 pathway.…”

Decorin as a possible strategy for the amelioration of COVID-19

“…They showed that the deposition of fibronectin is repressed by decorin when HPMC were unveiled to peritoneal dialysis fluid. This effect was carried out by the downregulation of TGF-β1 and enhanced phosphorylation of glycogen synthase kinase 3 beta (GSK-3β) [22] .…”

The Preventive Effect of Decorin on Epidural Fibrosis and Epidural Adhesions After Laminectomy

“…We hypothesized that decreased decorin might contribute to the pathogenesis of epidural fibrosis and epidural adhesions. A variety of researches employing recombinant decorin or decorin gene therapy have demonstrated that decorin has anti-fibrosis activity in scar formation or fibrosis models in many organs ( Li et al, 2004 ; Jang et al, 2016 ; Chouhan et al, 2019 ; Cianfarani et al, 2019 ; Jiang et al, 2020 ). Chouhan et al ( 2019 ) synthesized a hydrogel that can sustain the release of decorin and significantly inhibit corneal scar formation.…”