title: Activation of hypoxia-inducible factor by cobalt is associated with the attenuation of tissue injury and apoptosis in cyclosporine-induced nephropathy.
abstract: Hypoxia-inducible factor (HIF) is a transcription factor that regulates cellular hypoxic responses.  Despite the therapeutic benefits of cyclosporine A (CsA) in organ transplantation, its clinical use is limited due to chronic nephropathy.  We investigated whether HIF activation by cobalt could improve CsA-induced nephropathy, and investigated the related mechanism.  In animal experiments, rats were kept on a 0.05% low-salt diet and administered CsA subcutaneously for 28 days (15 mg/kg/day).  They also received cobalt (10 mg/kg/day) during the entire experimental period.  The administration of cobalt significantly increased HIF-1α expression in the kidney.  The increased expression of HIF-1α ameliorated CsA-induced afferent arteriolopathy and tubulointerstitial injury in the kidney.  Cobalt significantly reduced the infiltration of macrophages/monocytes into the renal tubulointerstitium.  In addition, HIF activation by cobalt reduced the number of CsA-induced apoptotic cells in the kidney.  Subsequently, HK-2 human renal tubular epithelial cells were used for in vitro experiments.  They were pre-treated with 150 µM of cobalt to activate HIF, and then exposed to 10 µM CsA.  HIF activation by cobalt decreased the CsA-induced apoptosis in HK-2 cells, as judged by the decreases in the number of apoptotic cells, pro-apoptotic caspase-3 activity, and the expression level of cleaved caspase-3, together with the increase in the expression of anti-apoptotic bcl-2.  Cobalt pretreatment also reduced the CsA-induced phosphorylation of NF-κB and the CsA-induced expression of vimentin and α-smooth muscle actin, suggesting the attenuation of inflammation and fibrosis.  In conclusion, the activation of HIF by cobalt may ameliorate the CsA-induced nephropathy by inhibiting apoptosis, inflammation, and fibrosis.
authors.affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Se Won
authors.initials: SW
authors.lastname: Oh
authors.forename: Jeong Myung
authors.initials: JM
authors.lastname: Ahn
authors.forename: Yun-Mi
authors.initials: YM
authors.lastname: Lee
authors.forename: Sejoong
authors.initials: S
authors.lastname: Kim
authors.forename: Ho Jun
authors.initials: HJ
authors.lastname: Chin
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Chae
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Na
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D003035:Cobalt / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007166:Immunosuppressive Agents; D003035:Cobalt; D016572:Cyclosporine; C018021:cobaltous chloride