Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury
Pinelopi P. Kapitsinou, … , Timothy A. Sutton, Volker H. Haase
Pinelopi P. Kapitsinou, … , Timothy A. Sutton, Volker H. Haase
Published May 1, 2014
Citation Information: J Clin Invest. 2014;124(6):2396-2409. https://doi.org/10.1172/JCI69073.
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Research Article Nephrology

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

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.

Authors

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

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Figure 2

Endothelial HIF protects from UUO-induced renal injury and inflammation.

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Endothelial HIF protects from UUO-induced renal injury and inflammation....
(A) Shown are representative Sirius red–stained kidney sections and corresponding quantification of Sirius red–positive areas at days 8 and 12 following UUO (n = 10–12). (B) Representative images of CD31-stained renal cortex or medulla from mutant and control kidneys (day 12 after UUO); panels on right show quantification of CD31-positive areas in cortex or medulla (n = 10) and corresponding Cd31 mRNA levels in UUO (day 12) and CTL kidneys from Hif1aHif2a–/– mice and controls. (C) Shown are F4/80-stained representative kidney sections from Hif1aHif2a–/– mutants and Cre– mice at day 12 following UUO (n = 10–11). Graph shows the number of F4/80-positive cells per hpf. Graph bars represent mean values ± SEM; *P < 0.05. UUO, kidney subjected to UUO; CTL, contralateral kidney. Scale bars: 100 μm.