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

• Published in: The Journal of clinical investigation Vol. 124; no. 6; pp. 2396 - 2409
• Main Authors: Kapitsinou, Pinelopi P, Sano, Hideto, Michael, Mark, Kobayashi, Hanako, Davidoff, Olena, Bian, Aihua, Yao, Bing, Zhang, Ming-Zhi, Harris, Raymond C, Duffy, Kevin J, Erickson-Miller, Connie L, Sutton, Timothy A, Haase, Volker H
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.06.2014
• Subjects: 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
• ISSN: 0021-9738; 1558-8238
• 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.