期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 124, 期 6, 页码 2396-2409出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI69073
关键词
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资金
- Krick-Brooks chair in Nephrology
- NIH [R01-DK081646, R01-DK007124]
- Vanderbilt University O'Brien Center [P30-DK07934]
- Indiana University O'Brien Center [P30-DK079312]
- AMGEN Nephrology Fellowship Grant
- American Heart Association National Scientist Development [11SDG5570023]
- Grants-in-Aid for Scientific Research [24591420] Funding Source: KAKEN
The hypoxia-inducible transcription factors HIP-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 HIP-1 and HIF-2 in response to ischemic kidney injury. Here, we used a genetic approach to specifically dissect the roles of endothelial HIP-1 and HIF-2 in murine models of hypoxic kidney injury induced by ischemia reperfusion or ureteral obstruction. In both models, inactivation of endothelial HIP increased injury-associated renal inflammation and fibrosis. Specifically, inactivation of endothelial HIF-2 alpha, but not endothelial HIF-1 alpha, 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 HIP via HIP prolyl-hydroxylase inhibition protected wild-type animals from ischemic kidney injury and inflammation; however, these same protective effects were not observed in HIP 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.
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