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 inhibitortreated 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.

Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury

“…17 Studies from our group 18,19 and others 20 have demonstrated that HIF-2a plays a key protective role in renal IRI, by preserving endothelial integrity and functions. However, whether HIF-2a in T/NKT cells plays a role in renal IRI still remains to be elucidated.…”

Endothelial Krüppel-Like Factor 4 Mediates the Protective Effect of Statins against Ischemic AKI

“…In response to I/R, ECs increase the expression of cell adhesion molecules, such as vascular cell adhesion molecule 1 (Vcam1) and Icam1, which recruit and activate circulating inflammatory cells in the kidneys. [3][4][5][6][7] The results of previous studies have demonstrated that administration of blocking antibodies against Vcam1 or Icam1 ameliorated renal I/R injury in rodents. [3][4][5] Likewise, antisense oligonucleotides for Icam1 attenuated ischemic AKI in rats.…”

“…[3][4][5][6][7] The results of previous studies have demonstrated that administration of blocking antibodies against Vcam1 or Icam1 ameliorated renal I/R injury in rodents. [3][4][5] Likewise, antisense oligonucleotides for Icam1 attenuated ischemic AKI in rats. 6 Moreover, Kelly et al 7 showed that Icam1-deficient mice were protected from I/R injury to the kidneys.…”

Macrophages Aggravate Hypoxia-Induced Cardiac Microvascular Endothelial Cell Injury via Peroxynitrite: Protection by Tongxinluo

“…HIF-1a and HIF-2a are induced by hypoxia, which can drive VEGF expression, resulting in angiogenesis (Skuli et al, 2012;Kapitsinou et al, 2014;Oh et al, 2015). Contrary to iNOS, eNOS plays constitutive roles in physiological vasodilatation and ECE-1 is also an important regulator of vascular tone Robinson et al, 2014).…”

“…Mammalian HIFs function as heterodimers composed of either HIF-1a or HIF-2a bound to HIF-1b. HIF-1a appears to be ubiquitously expressed, whereas HIF-2a is more restricted to vascular endothelial cells (Skuli et al, 2012;Kapitsinou et al, 2014). HIFs control a series of genes that help in adaptation to hypoxia.…”