title: Lipopolysaccharide-induced cross-tolerance against renal ischemia-reperfusion injury is mediated by hypoxia-inducible factor-2α-regulated nitric oxide production.
abstract: Although the protective effect of lipopolysaccharide (LPS) pretreatment on renal ischemia/reperfusion injury is known, a link to hypoxia-inducible factors (HIFs) has not been established. Here we show that LPS treatment led to HIF-2α accumulation in mouse kidneys and endothelial cells, a result of nuclear factor-κB activation. Inactivation of HIF-2α, rather than HIF-1α, completely negated LPS-mediated protection against renal ischemia/reperfusion injury. LPS-stimulated renoprotection was related to inducible/endothelial nitric oxide synthase (iNOS/eNOS) expression, increased production of nitric oxide, and enhanced postischemic microcirculatory recovery. All these effects were lost in HIF-2α knockout mice. Preischemic administration of a nitric oxide donor, rather than erythropoietin, restored the lost preconditioning effect of LPS in HIF-2α knockout mice. In vitro and in vivo studies demonstrated that HIF-2α in endothelial cells, rather than myeloid cells or hepatocytes, was responsible for the LPS-mediated effects. Thus, our results demonstrated that LPS preconditioning protected against renal ischemia/reperfusion injury by HIF-2α activation in endothelial cells that subsequently improved renal microvascular perfusion and reduced ischemic tubular damage.
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Kang
authors.initials: K
authors.lastname: He
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Urology, Xuzhou Central Hospital, Xuzhou Medical University School of Clinical Medicine, Xuzhou, China.
authors.forename: Conghui
authors.initials: C
authors.lastname: Han
authors.affiliation: The Central Laboratory of Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Longmei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Transplantation and Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D019610:Cytoprotection; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D012079:Renal Circulation / Q000187:drug effects; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D052096:Warm Ischemia; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009569:Nitric Oxide; D020030:Nitric Oxide Donors; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse