title: Autophagy protects renal tubular cells against cyclosporine toxicity.
abstract: A major side effect of the powerful immunosuppressive drug cyclosporine (CsA) is the development of a chronic nephrotoxicity whose mechanisms are not fully understood. Recent data suggest that tubular cells play a central role in the pathogenesis of chronic nephropathies. We have shown that CsA is responsible for endoplasmic reticulum (ER) stress in tubular cells. Autophagy has recently been described to be induced by ER stress and to alleviate its deleterious effects. In this study, we demonstrate that CsA induces autophagy in primary cultured human renal tubular cells through LC3II expression and autophagosomes visualization by electron microscopy. Autophagy is dependant on ER stress because various ER stress inducers activate autophagy, and salubrinal, an inhibitor of eIF2alpha dephosphorylation that protects cells against ER stress, inhibited LC3II expression. Furthermore, autophagy inhibition during CsA treatment with beclin1 siRNA significantly increases tubular cell death. Finally, immunohistochemical analysis of rat kidneys demonstrates a positive LC3 staining on injured tubular cells, suggesting that CsA induces autophagy in vivo. Taken together, these results demonstrate that CsA, through ER stress induction, activates autophagy as a protection against cell death.
authors.affiliation: INSERM U775, Centre Universitaire des Saints-Pères, Université Paris Descartes, Paris, France. nicolas.pallet@univ-paris5.fr
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pallet
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bouvier
authors.forename: Christophe
authors.initials: C
authors.lastname: Legendre
authors.forename: Jerome
authors.initials: J
authors.lastname: Gilleron
authors.forename: Patrice
authors.initials: P
authors.lastname: Codogno
authors.forename: Philippe
authors.initials: P
authors.lastname: Beaune
authors.forename: Eric
authors.initials: E
authors.lastname: Thervet
authors.forename: Dany
authors.initials: D
authors.lastname: Anglicheau
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D016572:Cyclosporine / Q000633:toxicity*; D019610:Cytoprotection / Q000187:drug effects*; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007684:Kidney Tubules / Q000166:cytology* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019284:Thapsigargin / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D015415:Biomarkers; D016572:Cyclosporine; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D019284:Thapsigargin; C491997:BECN1 protein, human; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP