title: Activation of hypoxia-inducible factor-1 ameliorates postischemic renal injury via inducible nitric oxide synthase.
abstract: Hypoxia-inducible factor-1 (HIF-1) could ameliorate renal ischemia reperfusion injury (IRI), but the underlying mechanism remains elusive. In the current study, we aim to investigate the possible role of prolyl hydroxylases inhibitor dimethyloxalylglycine (DMOG) in inducing delayed preconditioning-like effects against IRI. Mice were divided into four groups (n = 6): sham group; IRI group; DMOG group: pretreated with DMOG 24 h before IRI; and GW274150 + DMOG group: pretreated with DMOG followed by iNOS inhibitor GW274150 treatment 24 h before IRI. The results showed that the protein level of HIF-1a and the expression of its targets inducible nitric oxide synthase (iNOS), erythropoietin, and heme oxygenase-1 were obviously increased after administration of DMOG. Histological analysis of renal function showed improvement in tubulointerstitial injury due to ischemia by delayed preconditioning with DMOG. GW274150 antagonized the delayed renal protection afforded by DMOG as reflected by deteriorated renal dysfunction, aggravated histological injury, increased renal cell apoptosis, and increased vimentin expression in the kidney. In conclusion, our data demonstrate that DMOG pretreatment induces delayed renal protection against IRI in mice and the beneficial effects are mitigated by pharmacological inhibition of iNOS, suggesting that the protective effects derived from HIF-1 activation via DMOG in the kidney are partially mediated by iNOS.
authors.affiliation: Department of Nephrology, Huadong Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Zhang
authors.forename: Zhen-Wen
authors.initials: ZW
authors.lastname: Yan
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Sheng
authors.forename: Jing
authors.initials: J
authors.lastname: Xiao
authors.forename: Zhen-Xing
authors.initials: ZX
authors.lastname: Zhang
authors.forename: Zhi-Bin
authors.initials: ZB
authors.lastname: Ye
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D015427:Reperfusion Injury / Q000097:blood / Q000201:enzymology* / Q000473:pathology*; D013440:Sulfides / Q000494:pharmacology; D014746:Vimentin / Q000378:metabolism
chemical_list: D000600:Amino Acids, Dicarboxylic; D051793:Hypoxia-Inducible Factor 1; D020011:Protective Agents; D013440:Sulfides; D014746:Vimentin; C409004:GW 274150; D003404:Creatinine; D052247:Nitric Oxide Synthase Type II; C040947:oxalylglycine