title: Endoplasmic reticulum stress as a novel target to ameliorate epithelial-to-mesenchymal transition and apoptosis of human peritoneal mesothelial cells.
abstract: Epithelial-to-mesenchymal transition (EMT) and apoptosis of peritoneal mesothelial cells are known to be the earliest mechanisms of peritoneal fibrosis in peritoneal dialysis (PD). Endoplasmic reticulum (ER) stress with an unfolded protein response is 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 peritoneal fibrosis, we examined the effect of ER stress on EMT or apoptosis of human peritoneal mesothelial 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 response to protect HPMCs from EMT and apoptosis. Peritoneal mesothelial 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 peritoneal damage in PD patients.
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Ewha Medical Research Center, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Shin
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Ewha Medical Research Center, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Eun-Sun
authors.initials: ES
authors.lastname: Ryu
authors.affiliation: Department of Life Sciences, Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Eok-Soo
authors.initials: ES
authors.lastname: Oh
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Ewha Medical Research Center, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Duk-Hee
authors.initials: DH
authors.lastname: Kang
mesh_terms: D000900:Anti-Bacterial Agents / Q000009:adverse effects; D017209:Apoptosis; D001202:Ascitic Fluid / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D058750:Epithelial-Mesenchymal Transition; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D049990:Membrane Transport Modulators / Q000009:adverse effects; D008954:Models, Biological; D019913:Nuclear Localization Signals / Q000187:drug effects / Q000378:metabolism; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D056627:Peritoneal Fibrosis / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D019284:Thapsigargin / Q000009:adverse effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014415:Tunicamycin / Q000009:adverse effects; D056811:Unfolded Protein Response; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; C495270:CTNNB1 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D049990:Membrane Transport Modulators; D019913:Nuclear Localization Signals; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D014415:Tunicamycin; D019284:Thapsigargin