Endoplasmic reticulum stress as a novel target to ameliorate epithelial-to-mesenchymal transition and apoptosis of human peritoneal mesothelial cells

Epithelial-to-mesenchymal transition (EMT) and apoptosis of peritonealmesothelial cells are known to be the earliest mechanisms of peritonealfibrosis in peritonealdialysis (PD). Endoplasmic reticulum (ER) stress with an unfolded protein responseis regarded to have a role in the development of organ fibrosis. To investigate the potential role of ER stress as a target to prevent and/or delay the development of peritonealfibrosis, we examined the effect of ER stress on EMT or apoptosis of human peritonealmesothelial cells (HPMCs) and elucidated the mechanisms underlying the protective effect of ER stress preconditioning on TGF-β1-induced EMT. ER stress inducers, tunicamycin(TM) and thapsigargin(TG), induced EMT with Smad2/3 phosphorylation, an increased nuclear translocation of β-catenin and Snail expression. Low concentrations of TM and TG did not induce apoptosis within 48 h; however, high concentrations of TM- (>1 ng/ml) and TG- (>1 nM) induced apoptosis at 12 h with a persistent increase in C/EBP homologous protein. TGF-β1 induced EMT and apoptosis in HPMCs, which was ameliorated by taurine-conjugated ursodeoxycholic acid, an ER stress blocker. Interestingly, pre-treatment with TM or TG for 4 h also protected the cells from TGF-β1-induced EMT and apoptosis, demonstrating the role of ER stress as an adaptive responseto protectHPMCs from EMT and apoptosis. Peritonealmesothelial cells isolated from PD patients displayed an increase in GRP78/94, which was correlated with the degree of EMT. These findings suggest that the modulation of ER stress in HPMCs could serve as a novel approach to ameliorate peritonealdamage in PD patients.