title: Ochratoxin A induces ER stress and apoptosis in mesangial cells via a NADPH oxidase-derived reactive oxygen species-mediated calpain activation pathway.
abstract: Ochratoxin A (OTA) contaminated food increases reactive oxygen species (ROS) production in glomerulus and causes glomerulopathy. The molecular mechanisms still remain uncertain. In this study, we used mouse and rat glomerular mesangial cells and delineate the signaling pathway behind the OTA-triggered cell apoptosis. OTA dose-dependently induced expression of ER stress markers including phospho-PERK, phospho-eIF2α, GRP78, GRP94, and CHOP. Apoptosis events including cleavage of caspase-12, caspase-7, and PARP are also observed. OTA activated oxidative stress and increased NADPH oxidase activity. NADPH oxidase inhibitor, apocynin, significantly attenuated OTA-induced cell apoptosis. Moreover, OTA markedly increased the calpain activity which significantly inhibited by apocynin. Transfection of calpain-siRNA effectively inhibited the OTA-increased ER stress-related protein expression. These findings suggest that OTA activated NADPH oxidase and calpain, induced ER stress and ROS production, and caused glomerular mesangial cells apoptosis which leads to glomerulopathy.
authors.affiliation: Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.|Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.|Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Meei-Ling
authors.initials: ML
authors.lastname: Sheu
authors.affiliation: Chemical Engineering Division, Institute of Nuclear Energy Research, Atomic Energy Council, Longtan District, Taoyuan, Taiwan.
authors.forename: Chin-Chang
authors.initials: CC
authors.lastname: Shen
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yuan-Siao
authors.initials: YS
authors.lastname: Chen
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chih-Kang
authors.initials: CK
authors.lastname: Chiang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002154:Calpain / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism*; D009793:Ochratoxins / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002121:Calcium Channel Blockers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D009793:Ochratoxins; D017382:Reactive Oxygen Species; C025589:ochratoxin A; D019255:NADPH Oxidases; D002154:Calpain
keywords: ER stress; NADPH oxidase; apoptosis; mesangial cells; ochratoxin A