Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury.

Kapitsinou PP, Sano H, Michael M, Kobayashi H, Davidoff O, Bian A, Yao B, Zhang MZ, Harris RC, Duffy KJ, Erickson-Miller CL, Sutton TA, Haase VH
J Clin Invest. 2014 124 (6): 2396-409

PMID: 24789906 · PMCID: PMC4092875 · DOI:10.1172/JCI69073

The hypoxia-inducible transcription factors HIF-1 and HIF-2 mediate key cellular adaptions to hypoxia and contribute to renal homeostasis and pathophysiology; however, little is known about the cell type-specific functions of HIF-1 and HIF-2 in response to ischemic kidney injury. Here, we used a genetic approach to specifically dissect the roles of endothelial HIF-1 and HIF-2 in murine models of hypoxic kidney injury induced by ischemia reperfusion or ureteral obstruction. In both models, inactivation of endothelial HIF increased injury-associated renal inflammation and fibrosis. Specifically, inactivation of endothelial HIF-2α, but not endothelial HIF-1α, resulted in increased expression of renal injury markers and inflammatory cell infiltration in the postischemic kidney, which was reversed by blockade of vascular cell adhesion molecule-1 (VCAM1) and very late antigen-4 (VLA4) using monoclonal antibodies. In contrast, pharmacologic or genetic activation of HIF via HIF prolyl-hydroxylase inhibition protected wild-type animals from ischemic kidney injury and inflammation; however, these same protective effects were not observed in HIF prolyl-hydroxylase inhibitor-treated animals lacking endothelial HIF-2. Taken together, our data indicate that endothelial HIF-2 protects from hypoxia-induced renal damage and represents a potential therapeutic target for renoprotection and prevention of fibrosis following acute ischemic injury.

MeSH Terms (21)

Animals Basic Helix-Loop-Helix Transcription Factors Disease Models, Animal Endothelial Cells Fibrosis Humans Human Umbilical Vein Endothelial Cells Hypoxia-Inducible Factor-Proline Dioxygenases Hypoxia-Inducible Factor 1, alpha Subunit Integrin alpha4beta1 Ischemia Kidney Male Mice Mice, 129 Strain Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Reperfusion Injury Ureteral Obstruction Vascular Cell Adhesion Molecule-1

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