Journal Article

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

Kobayashi, Hanako, Michael, Mark, Sano, Hideto, Zhang, Ming-Zhi, Kapitsinou, Pinelopi P., Haase, Volker H., Harris, Raymond C., Bian, Aihua, Yao, Bing, Duffy, Kevin J., Davidoff, Olena, Erickson-Miller, Connie L., Sutton, Timothy A.

2014

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Basic Helix-Loop-Helix Transcription Factors - deficiency / Basic Helix-Loop-Helix Transcription Factors - genetics / Basic Helix-Loop-Helix Transcription Factors - physiology / Biological control systems / Biomedical research / Cloning / Disease Models, Animal / Endothelial Cells - physiology / Endothelium / Fibrosis / Gene mutations / Genetic aspects / Human Umbilical Vein Endothelial Cells / Humans / Hypoxia / 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 / Injuries / Integrin alpha4beta1 - antagonists & inhibitors / Integrin alpha4beta1 - physiology / Ischemia / Ischemia - pathology / Ischemia - physiopathology / Ischemia - prevention & control / Kidney - blood supply / Kidney - injuries / Kidney - physiopathology / Kidneys / Lungs / Male / Mice / Mice, 129 Strain / Mice, Inbred BALB C / Mice, Inbred C57BL / Mice, Knockout / Mortality / Pathogenesis / Permeability / Physiological aspects / Reperfusion Injury - pathology / Reperfusion Injury - physiopathology / Reperfusion Injury - prevention & control / Rodents / Software / Studies / Ureteral Obstruction - complications / Vascular Cell Adhesion Molecule-1 - physiology / Vascular endothelium