Endothelial PHD2/HIF Axis in Ischemic Kidney Injury and Inflammation

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PROJECT SUMMARY Acute kidney injury (AKI) due to ischemia is a common clinical condition, which is associated with poor patient outcomes, including high risk for mortality and development of chronic kidney disease. Following ischemic AKI, peritubular endothelial cells contribute to tissue injury by promoting inflammation and interfere with renal recovery through impaired revascularization. Key regulators of hypoxic vascular responses are Hypoxia- Inducible-Factors (HIF)-1 and –2, transcriptional factors whose activity is inhibited by proly-hydroxylase domain proteins 1 to 3 (PHD1 to PHD3), PHD2 being the main oxygen sensor. Our recent study was the first to identify a crucial role for endothelial PHD2 in post-ischemic renal injury but the underlying molecular mechanisms remain undefined. Identification of the mechanisms whereby endothelial PHD2 regulates post-ischemic renal injury and inflammation may create novel and targeted therapeutic opportunities in the field of AKI. In this proposal, we hypothesize that inhibition of endothelial PHD2 suppresses post-ischemic renal inflammation and promotes revascularization through HIF-dependent induction of metabolic reprogramming in endothelial cells. To test this hypothesis, we propose three specific aims. Aim 1 defines the role of endothelial PHD2/HIF axis in post-ischemic kidney injury and inflammation by investigating how disrupting HIF-1 or HIF-2 affects the post- ischemic kidney microenvironment in the context of endothelial PHD2 deficiency. Aim 2 examines the role of endothelial PHD2/HIF signaling in post-ischemic kidney repair and revascularization using genetic models, which allow acute endothelial specific inactivation of PHD2 alone and concurrently with either HIF-1 or HIF-2 after the induction of ischemic kidney injury. Aim 3 defines how alterations in glycolysis and mitochondrial respiration induced by hypoxic signaling affect endothelial inflammatory and angiogenic responses. The proposed research is innovative because we investigate the role of PHD2/HIF pathway in endothelial cells, a neglected cell type in the field of AKI, using powerful genetic models. Furthermore, state-of–the art cell culture techniques are employed to determine endothelial phenotypes resulting from PHD2/HIF-mediated metabolic reprogramming. Upon conclusion, we will obtain fundamentally new insights into how endothelial PHD2/HIF axis affects post-ischemic kidney injury outcomes.