Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury.
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.
Pinelopi P
PP
Kapitsinou
Hideto
H
Sano
Mark
M
Michael
Hanako
H
Kobayashi
Olena
O
Davidoff
Aihua
A
Bian
Bing
B
Yao
Ming-Zhi
MZ
Zhang
Raymond C
RC
Harris
Kevin J
KJ
Duffy
Connie L
CL
Erickson-Miller
Timothy A
TA
Sutton
Volker H
VH
Haase
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000502:physiology; D005355:Fibrosis; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors / Q000502:physiology; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D007668:Kidney / Q000098:blood supply / Q000293:injuries* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D014517:Ureteral Obstruction / Q000150:complications; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D039041:Integrin alpha4beta1; D019010:Vascular Cell Adhesion Molecule-1; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse