title: Induction of renoprotective gene expression by cobalt ameliorates ischemic injury of the kidney in rats.
abstract: Hypoxia in the tubulointerstitium has been thought to play pivotal roles in the pathophysiology of acute renal failure and the progression of chronic kidney disease. Pre-induction of hypoxia-inducible and renoprotective gene expression may protect subsequent ischemic injury. This study evaluated the efficacy of cobalt, which inhibits HIF-1 degradation and increases the expression level of hypoxia-related genes, in an acute ischemic tubulointerstitial injury model of rats. Ischemic renal injury was induced by 45-min clamping of renal pedicles with contralateral nephrectomy. Elevation of serum creatinine and morphologic injury after the ischemic insult was observed. Administration of cobalt chloride afforded striking functional improvement (mean +/- SEM creatinine in mg/dl: Co treatment group, 2.14 +/- 1.21; control, 3.69 +/- 1.43; P < 0.05) associated with amelioration of tubulointerstitial damage. Cobalt treatment also reduced macrophage infiltration significantly. In the kidney of rats treated with cobalt, mRNA levels of several genes that serve for tissue protection, such as HO-1, EPO, Glut-1, and VEGF, were increased before ischemic injury. Upregulation of HO-1 by cobalt was confirmed at the protein level. Subcutaneous injection of cobalt also ameliorated ischemic injury, which was associated with upregulation of renal HIF-1alpha protein expression. These results suggest that protection against hypoxic tubulointerstitial injury by cobalt administration is mediated by induction of renoprotective gene expression. HIF induction is one possible and attractive explanation for the observed effects.
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: Makiko
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Makino
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ishizaka
authors.forename: Eisei
authors.initials: E
authors.lastname: Noiri
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003035:Cobalt / Q000378:metabolism / Q000494:pharmacology*; D003404:Creatinine / Q000097:blood; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D007511:Ischemia; D007668:Kidney / Q000293:injuries / Q000378:metabolism* / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D009687:Nuclear Proteins / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D003035:Cobalt; D003404:Creatinine; C018021:cobaltous chloride