title: Transient ureteral obstruction prevents against kidney ischemia/reperfusion injury via hypoxia-inducible factor (HIF)-2α activation.
abstract: Although the protective effect of transient ureteral obstruction (UO) prior to ischemia on subsequent renal ischemia/reperfusion (I/R) injury has been documented, the underlying molecular mechanism remains to be understood. We showed in the current study that 24 h of UO led to renal tubular hypoxia in the ipsilateral kidney in mice, with the accumulation of hypoxia-inducible factor (HIF)-2α, which lasted for a week after the release of UO. To address the functions of HIF-2α in UO-mediated protection of renal IRI, we utilized the Mx-Cre/loxP recombination system to knock out target genes. Inactivation of HIF-2α, but not HIF-1α blunted the renal protective effects of UO, as demonstrated by much higher serum creatinine level and severer histological damage. UO failed to prevent postischemic neutrophil infiltration and apoptosis induction in HIF-2α knockout mice, which also diminished the postobstructive up-regulation of the protective molecule, heat shock protein (HSP)-27. The renal protective effects of UO were associated with the improvement of the postischemic recovery of intra-renal microvascular blood flow, which was also dependent on the activation of HIF-2α. Our results demonstrated that UO protected the kidney via activation of HIF-2α, which reduced tubular damages via preservation of adequate renal microvascular perfusion after ischemia. Thus, preconditional HIF-2α activation might serve as a novel therapeutic strategy for the treatment of ischemic acute renal failure.
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Shun
authors.initials: S
authors.lastname: Zhang
authors.forename: Cong-Hui
authors.initials: CH
authors.lastname: Han
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: Chen
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Long-Mei
authors.initials: LM
authors.lastname: Xu
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Zhang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
mesh_terms: D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007674:Kidney Diseases / Q000517:prevention & control*; D007684:Kidney Tubules / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000517:prevention & control*; D013997:Time Factors; D014517:Ureteral Obstruction / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D055551:HSP27 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse