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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Kidney Injury / genetics
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Acute Kidney Injury / metabolism
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Acute Kidney Injury / physiopathology
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Acute Kidney Injury / prevention & control*
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Animals
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Basic Helix-Loop-Helix Transcription Factors / deficiency
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Bone Marrow Transplantation
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Cells, Cultured
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Cytoprotection
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Disease Models, Animal
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Endothelial Cells / drug effects
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Endothelial Cells / immunology
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Endothelial Cells / metabolism
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Enzyme Inhibitors / pharmacology
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / immunology
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Kidney / blood supply
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Kidney / drug effects*
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Kidney / metabolism
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Lipopolysaccharides / pharmacology*
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Male
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Mice
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Mice, Knockout
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Microcirculation / drug effects
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NF-kappa B / metabolism
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Nitric Oxide / metabolism*
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Nitric Oxide Donors / pharmacology
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Nitric Oxide Synthase Type II / antagonists & inhibitors
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Nitric Oxide Synthase Type II / metabolism
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Nitric Oxide Synthase Type III / antagonists & inhibitors
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Nitric Oxide Synthase Type III / metabolism
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RNA Interference
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Renal Circulation / drug effects
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Reperfusion Injury / genetics
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Reperfusion Injury / metabolism
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Reperfusion Injury / physiopathology
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Reperfusion Injury / prevention & control*
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Signal Transduction
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Time Factors
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Transfection
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Warm Ischemia
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Enzyme Inhibitors
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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Lipopolysaccharides
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NF-kappa B
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Nitric Oxide Donors
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endothelial PAS domain-containing protein 1
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Nitric Oxide
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Nitric Oxide Synthase Type II
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Nitric Oxide Synthase Type III
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Nos2 protein, mouse
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Nos3 protein, mouse