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.

HIF2α signaling inhibits adherens junctional disruption in acute lung injury

“…In this context, increased VE-PTP expression mediated by HIF2α promotes VE-cadherin interactions at AJs and thus strengthens the endothelial barrier. We observed that HIF2α-mediated VE-PTP expression was physiologically relevant and represented a fundamental adaptive response to tissue hypoxia and inflammation, both of which are characterized by stabilization and nuclear translocation of HIF2α (32). The importance of this mechanism was evident by the finding that EC-specific deletion of Hif2a (Hif2a EC-/-) in mice enhanced endothelial permeability as well as leukocyte extravasation in lungs secondary to inhibition of VE-PTP expression.…”

“…The contextual aspect of VE-PTP's role in stabilizing the endothelial barrier also needs to be considered in light of a recent study, which showed that inhibiting VE-PTP by a smallmolecule inhibitor stabilized the ocular vasculature in experimental models of retinal neovascularization (30). In that study, the barrier-stabilizing effects of VE-PTP inhibition were attributed to suppression of VEGF-induced permeability as well as increased TIE2 activation, because TIE2 is a binding partner of VE-PTP (32). Our observation that VE-PTP activation stabilizes the endothelial barrier may be explained by differences in TIE2 and VEGF signaling in the ocular vasculature undergoing angiogenesis and by the lung endothelium responding to acute endotoxin-mediated injury.…”

Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury

“…19 In this study, a combination of LPS/CGS21680 reduced the renal injury to a surprising extent in WT mice, but had no effect in Mx1-HIF-2a …”

“…19 Lck-Cre (stock number: 003802), Mx1-Cre (003556) transgene mice, HIF-2a floxed mice (008407), as well as Rag1KO mice (002216) were all from The Jackson Laboratory (Bar Harbor, ME). The mating strategy, genotyping and the confirmation of target gene excision are described in the Supplemental Material.…”

“…17 Studies from our group 18,19 and others 20 have demonstrated that HIF-2a plays a key protective role in renal IRI, by preserving endothelial integrity and functions. However, whether HIF-2a in T/NKT cells plays a role in renal IRI still remains to be elucidated.…”