Loosening of the mesothelial barrier as an early therapeutic target to preserve peritoneal function in peritoneal dialysis

Abstract

Phenotype transition of peritoneal mesothelial cells (MCs) including the epithelial-to-mesenchymal transition (EMT) is regarded as an early mechanism of peritoneal dysfunction and fibrosis in peritoneal dialysis (PD), producing proinflammatory and pro-fibrotic milieu in the intra-peritoneal cavity. Loosening of intercellular tight adhesion between adjacent MCs as an initial process of EMT creates the environment where mesothelium and submesothelial tissue are more vulnerable to the composition of bio-incompatible dialysates, reactive oxygen species, and inflammatory cytokines. In addition, down-regulation of epithelial cell markers such as E-cadherin facilitates de novo acquisition of mesenchymal phenotypes in MCs and production of extracellular matrices. Major mechanisms underlying the EMT of MCs include induction of oxidative stress, pro-inflammatory cytokines, endoplasmic reticulum stress and activation of the local renin-angiotensin system. Another mechanism of peritoneal EMT is mitigation of intrinsic defense mechanisms such as the peritoneal antioxidant system and anti-fibrotic peptide production in the peritoneal cavity. In addition to use of less bio-incompatible dialysates and optimum treatment of peritonitis in PD, therapies to prevent or alleviate peritoneal EMT have demonstrated a favorable effect on peritoneal function and structure, suggesting that EMT can be an early interventional target to preserve peritoneal integrity.

Keywords: Adhesion molecule; Epithelial-to-mesenchymal transition; Peritoneal fibrosis; Peritoneal mesothelial cells.

Figure 1. Epithelial-to-mesenchymal transition (EMT) as a key mechanism of peritoneal fibrosis.

Transition of epithelial cells (peritoneal mesothelial cells [MCs]) toward a mesenchymal phenotype can be initiated by alteration of peritoneal milieu induced by the peritoneal dialysis process and related pro-inflammatory and pro-oxidative stress. Loss of cell-to-cell contact and cell polarity is one of the earliest phenomena of this continuous process and is associated with down-regulation of adhesion components between adjacent epithelial cells. Loosening of cell contacts per se leads to de novo acquisition of mesenchymal phenotypes. Cells in the process of transition before invasion beyond the basement membrane and migration into the submesothelial zone (“Partial EMT,” green arrow) can be re-differentiated into MCs (mesenchymal-to-epithelial transition [MET], blue arrow) through either removal of EMT-inducing stimuli or reinforcement of the intraperitoneal defense mechanism. Instead of halting the process of phenotype transition of MCs, EMT may result in formation of myofibroblasts with production of extracellular matrices, which seems to be irreversible and results in peritoneal fibrosis. SMA, smooth muscle actin.