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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 Article has an altmetric score of 20

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

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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 1

Characterization of mice with EC-specific inactivation of HIF-1α and HIF-2α.

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Characterization of mice with EC-specific inactivation of HIF-1α and HIF...
(A) Scheme illustrating the strategy used to assess the degree of EC-specific recombination. Cdh5-Cre mice were crossed to ROSA26-ACTB-tdTomato,-EGFP reporter (mT/mG) mice, and ECs were analyzed by FACS. Graph on the right shows the percentage of GFP-positive cells contained within the CD31-positive/CD45-negative cell population isolated from kidneys or lungs. (B) Left: representative images of CD31-stained cortex and medulla of kidneys from EC-specific Hif1aHif2a–/– and Cre– control mice. Right: quantification of CD31-positive area (n = 5). (C) Shown are representative images of cablin-stained peritubular capillaries in renal cortex and medulla imaged with confocal laser-scanning microscopy. The anti-cablin antibody used here preferentially stains the basal lamina of peritubular renal capillaries and does not label glomerular capillaries or small arterioles. (D) Quantification of baseline vascular permeability in kidney and lung tissue from 8-week-old mice using the EBD vascular permeability assay (n = 4–6). Graph bars represent mean values ± SEM; *P < 0.05. Scale bars: 100 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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