title: Endoplasmic reticulum stress mediates aristolochic acid I-induced apoptosis in human renal proximal tubular epithelial cells.
abstract: Aristolochic acid (AA), derived from the Aristolochia species, has been associated with aristolochic acid nephropathy (AAN), which has emerged as a worldwide disease. Aristolochic acid I (AAI) is the main ingredient of AA, and the underlying mechanisms for AAI-induced nephrotoxicity are still unclear. In this study, we investigated whether endoplasmic reticulum (ER) stress was involved in AAI-induced nephrotoxicity. The results showed that treatment of HK-2 cells (a human proximal tubular epithelial cell line) with AAI caused an increase in eukaryotic initiation factor-2α (eIF2α) phosphorylation, X-box binding protein 1 (XBP1) mRNA splicing and the expression of glucose-regulated protein (GRP) 78 and CAAT/enhancer-binding protein-homologous protein (CHOP). These events represent typical markers of the ER stress-related signaling pathway. Pretreatment with 4-phenylbutyrate (4-PBA) or salubrinal (Sal) significantly inhibited AAI-induced apoptosis, indicating the role of ER stress in AAI-induced apoptosis. In addition, AAI-induced cell death followed an increase of reactive oxygen species (ROS) formation in HK-2 cells. Pretreatment with N-acetyl cysteine (NAC) or glutathione (GSH) significantly inhibited AAI-induced ER stress proteins and cell death, suggesting that ROS mediate AAI-induced ER stress. Taken together, these results suggest that the ER stress response is involved in apoptosis induced by AAI in HK-2 cells, thus offering a new insight into the nephrotoxicity of AAI.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Zhu
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.forename: Cuiwen
authors.initials: C
authors.lastname: Guan
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.forename: Chen
authors.initials: C
authors.lastname: Xi
authors.forename: Zizhang
authors.initials: Z
authors.lastname: Ouyang
authors.forename: Meiwan
authors.initials: M
authors.lastname: Chen
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Qiu
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Huang
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects*; D034341:Aristolochic Acids / Q000633:toxicity*; D002082:Butylamines / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002934:Cinnamates / Q000494:pharmacology; D053938:DNA Fragmentation; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism
chemical_list: C121358:4-phenylbutylamine; C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D034341:Aristolochic Acids; D002082:Butylamines; D002934:Cinnamates; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C496827:salubrinal; D051742:Transcription Factor CHOP; C000228:aristolochic acid I; D053148:Caspase 3; D013890:Thiourea