title: ER stress contributes to renal proximal tubule injury by increasing SREBP-2-mediated lipid accumulation and apoptotic cell death.
abstract: Renal proximal tubule injury is induced by agents/conditions known to cause endoplasmic reticulum (ER) stress, including cyclosporine A (CsA), an immunosuppressant drug with nephrotoxic effects. However, the underlying mechanism by which ER stress contributes to proximal tubule cell injury is not well understood. In this study, we report lipid accumulation, sterol regulatory element-binding protein-2 (SREBP-2) expression, and ER stress in proximal tubules of kidneys from mice treated with the classic ER stressor tunicamycin (Tm) or in human renal biopsy specimens showing CsA-induced nephrotoxicity. Colocalization of ER stress markers [78-kDa glucose regulated protein (GRP78), CHOP] with SREBP-2 expression and lipid accumulation was prominent within the proximal tubule cells exposed to Tm or CsA. Prolonged ER stress resulted in increased apoptotic cell death of lipid-enriched proximal tubule cells with colocalization of GRP78, SREBP-2, and Ca(2+)-independent phospholipase A(2) (iPLA(2)β), an SREBP-2 inducible gene with proapoptotic characteristics. In cultured HK-2 human proximal tubule cells, CsA- and Tm-induced ER stress caused lipid accumulation and SREBP-2 activation. Furthermore, overexpression of SREBP-2 or activation of endogenous SREBP-2 in HK-2 cells stimulated apoptosis. Inhibition of SREBP-2 activation with the site-1-serine protease inhibitor AEBSF prevented ER stress-induced lipid accumulation and apoptosis. Overexpression of the ER-resident chaperone GRP78 attenuated ER stress and inhibited CsA-induced SREBP-2 expression and lipid accumulation. In summary, our findings suggest that ER stress-induced SREBP-2 activation contributes to renal proximal tubule cell injury by dysregulating lipid homeostasis.
authors.affiliation: Hamilton Centre for Kidney Research, St. Joseph's Healthcare Hamilton, 50 Charlton Ave. East, Hamilton, Ontario, Canada.
authors.forename: Sárka
authors.initials: S
authors.lastname: Lhoták
authors.forename: Sudesh
authors.initials: S
authors.lastname: Sood
authors.forename: Elise
authors.initials: E
authors.lastname: Brimble
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Carlisle
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Colgan
authors.forename: Adam
authors.initials: A
authors.lastname: Mazzetti
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Dickhout
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Ingram
authors.forename: Richard C
authors.initials: RC
authors.lastname: Austin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001706:Biopsy; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051782:Sterol Regulatory Element Binding Protein 2 / Q000187:drug effects / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D014415:Tunicamycin; D016572:Cyclosporine