title: Chronic hypoxia aggravates renal injury via suppression of Cu/Zn-SOD: a proteomic analysis.
abstract: Accumulating evidence suggests a pathogenic role of chronic hypoxia in various kidney diseases. Chronic hypoxia in the kidney was induced by unilateral renal artery stenosis, followed 7 days later by observation of tubulointerstitial injury. Proteomic analysis of the hypoxic kidney found various altered proteins. Increased proteins included lipocortin-5, calgizzarin, ezrin, and transferrin, whereas the decreased proteins were alpha(2u)-globulin PGCL1, eukaryotic translation elongation factor 1alpha(2), and Cu/Zn superoxide dismutase (SOD1). Among these proteins, we focused on Cu/Zn-SOD, a crucial antioxidant. Western blot analysis and real-time quantitative PCR analysis confirmed the downregulation of Cu/Zn-SOD in the chronic hypoxic kidney. Furthermore, our laser capture microdissection system showed that the expression of Cu/Zn-SOD was predominant in the tubulointerstitium and was decreased by chronic hypoxia. The tubulointerstitial injury estimated by histology and immunohistochemical markers was ameliorated by tempol, a SOD mimetic. This amelioration was associated with a decrease in levels of the oxidative stress markers 4-hydroxyl-2-nonenal and nitrotyrosine. Our in vitro studies utilizing cultured tubular cells revealed a role of TNF-alpha in downregulation of Cu/Zn-SOD. Since the administration of anti-TNF-alpha antibody ameliorated Cu/Zn-SOD suppression, TNF-alpha seems to be one of the suppressants of Cu/Zn-SOD. In conclusion, our proteomic analysis revealed a decrease in Cu/Zn-SOD, at least partly by TNF-alpha, in the chronic hypoxic kidney. This study, for the first time, uncovered maladaptive suppression of Cu/Zn-SOD as a mediator of a vicious cycle of oxidative stress and subsequent renal injury induced by chronic hypoxia.
authors.affiliation: Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Son
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kojima
authors.forename: Reiko
authors.initials: R
authors.lastname: Inagi
authors.forename: Makiko
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D008297:Male; D009395:Nephritis, Interstitial / Q000201:enzymology* / Q000503:physiopathology*; D018384:Oxidative Stress / Q000502:physiology; D040901:Proteomics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012078:Renal Artery Obstruction / Q000150:complications / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013482:Superoxide Dismutase