Limiting hypoxia-induced renal damage
Acute hypoxia-induced renal injury often progresses to chronic kidney disease (CKD), and the subsequent loss of kidney function is linked to endothelial cell (EC) damage. The hypoxia-inducible transcription factors HIF-1 and HIF-2 are expressed in renal ECs following ischemic injury, but the specific contributions of these mediators to pathogenesis are not clear. Using murine models of hypoxic kidney injury, Pinelopi Kapitsinou and colleagues at the Vanderbilt University School of Medicine evaluated changes in the post-ischemic kidneys from animals lacking both HIF-1 and HIF-2 in ECs. Loss of HIF-2 alone markedly increased kidney inflammation and fibrosis following ischemic injury and was associated with increased expression of the neutrophil adhesion molecule VCAM1. Blocking VCAM1 in HIF-2-deficient mice reduced hypoxia-associated phenotypes. Furthermore, enhancing HIF-2 activation in WT mice prior to ischemia and reperfusion protected animals from kidney injury. Together, these data indicate that endothelial HIF-2 protects kidney from hypoxia-induced damage. The accompanying image reveals the location of ECs (green) within the kidney of a reporter mouse strain.
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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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ISSN: 0021-9738 (print), 1558-8238 (online)