title: Endoplasmic Reticulum Stress-Induced Autophagy Provides Cytoprotection from Chemical Hypoxia and Oxidant Injury and Ameliorates Renal Ischemia-Reperfusion Injury.
abstract: We examined whether endoplasmic reticulum (ER) stress-induced autophagy provides cytoprotection from renal tubular epithelial cell injury due to oxidants and chemical hypoxia in vitro, as well as from ischemia-reperfusion (IR) injury in vivo. We demonstrate that the ER stress inducer tunicamycin triggers an unfolded protein response, upregulates ER chaperone Grp78, and activates the autophagy pathway in renal tubular epithelial cells in culture. Inhibition of ER stress-induced autophagy accelerated caspase-3 activation and cell death suggesting a pro-survival role of ER stress-induced autophagy. Compared to wild-type cells, autophagy-deficient MEFs subjected to ER stress had enhanced caspase-3 activation and cell death, a finding that further supports the cytoprotective role of ER stress-induced autophagy. Induction of autophagy by ER stress markedly afforded cytoprotection from oxidants H2O2 and tert-Butyl hydroperoxide and from chemical hypoxia induced by antimycin A. In contrast, inhibition of ER stress-induced autophagy or autophagy-deficient cells markedly enhanced cell death in response to oxidant injury and chemical hypoxia. In mouse kidney, similarly to renal epithelial cells in culture, tunicamycin triggered ER stress, markedly upregulated Grp78, and activated autophagy without impairing the autophagic flux. In addition, ER stress-induced autophagy markedly ameliorated renal IR injury as evident from significant improvement in renal function and histology. Inhibition of autophagy by chloroquine markedly increased renal IR injury. These studies highlight beneficial impact of ER stress-induced autophagy in renal ischemia-reperfusion injury both in vitro and in vivo.
authors.affiliation: Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Bhavya B
authors.initials: BB
authors.lastname: Chandrika
authors.affiliation: Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Cheng
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ou
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Djamali
authors.initials: D
authors.lastname: Muhoza
authors.affiliation: Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America.
authors.forename: Alexandrea F
authors.initials: AF
authors.lastname: Holmes
authors.affiliation: Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America.
authors.forename: Sue
authors.initials: S
authors.lastname: Theus
authors.affiliation: Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Sarika
authors.initials: S
authors.lastname: Deshmukh
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America; Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America.
authors.forename: Randy S
authors.initials: RS
authors.lastname: Haun
authors.affiliation: Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America; Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Gur P
authors.initials: GP
authors.lastname: Kaushal
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D019610:Cytoprotection / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016877:Oxidants / Q000009:adverse effects; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000627:therapeutic use*; D051437:Renal Insufficiency / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014415:Tunicamycin / Q000627:therapeutic use*; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D016877:Oxidants; D020011:Protective Agents; D014415:Tunicamycin; D000255:Adenosine Triphosphate; D020169:Caspases