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: Kang He, Xiaosong Chen, Conghui Han, Longmei Xu, Jianjun Zhang, Ming Zhang, Qiang Xia
• Journal: Kidney international (Kidney Int) Vol. 85 Issue 2 Pg. 276-88 (Feb 2014) ISSN: 1523-1755 [Electronic] United States
• PMID: 24025643 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Enzyme Inhibitors
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Lipopolysaccharides
• NF-kappa B
• Nitric Oxide Donors
• endothelial PAS domain-containing protein 1
• Nitric Oxide
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Nos2 protein, mouse
• Nos3 protein, mouse

Topics

• Acute Kidney Injury (genetics, metabolism, physiopathology, prevention & control)
• Animals
• Basic Helix-Loop-Helix Transcription Factors (deficiency, genetics, metabolism)
• Bone Marrow Transplantation
• Cells, Cultured
• Cytoprotection
• Disease Models, Animal
• Endothelial Cells (drug effects, immunology, metabolism)
• Enzyme Inhibitors (pharmacology)
• Human Umbilical Vein Endothelial Cells (drug effects, immunology, metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Kidney (blood supply, drug effects, metabolism)
• Lipopolysaccharides (pharmacology)
• Male
• Mice
• Mice, Knockout
• Microcirculation (drug effects)
• NF-kappa B (metabolism)
• Nitric Oxide (metabolism)
• Nitric Oxide Donors (pharmacology)
• Nitric Oxide Synthase Type II (antagonists & inhibitors, metabolism)
• Nitric Oxide Synthase Type III (antagonists & inhibitors, metabolism)
• RNA Interference
• Renal Circulation (drug effects)
• Reperfusion Injury (genetics, metabolism, physiopathology, prevention & control)
• Signal Transduction
• Time Factors
• Transfection
• Warm Ischemia