Endothelial HIF-2 Mediates Protection and Recovery From Ischemic Kidney Injury

J Clin Invest. 2014 Jun;124(6):2396-409. doi: 10.1172/JCI69073. Epub 2014 May 1.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / deficiency
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / physiology*
  • Disease Models, Animal
  • Endothelial Cells / physiology
  • Fibrosis
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / deficiency
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology
  • Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors
  • Integrin alpha4beta1 / antagonists & inhibitors
  • Integrin alpha4beta1 / physiology
  • Ischemia / pathology
  • Ischemia / physiopathology*
  • Ischemia / prevention & control
  • Kidney / blood supply
  • Kidney / injuries*
  • Kidney / physiopathology*
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Reperfusion Injury / pathology
  • Reperfusion Injury / physiopathology
  • Reperfusion Injury / prevention & control
  • Ureteral Obstruction / complications
  • Vascular Cell Adhesion Molecule-1 / physiology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Integrin alpha4beta1
  • Vascular Cell Adhesion Molecule-1
  • endothelial PAS domain-containing protein 1
  • Hypoxia-Inducible Factor-Proline Dioxygenases