Harnessing hypoxia responses to treat postischemic kidney injury and inflammation

Currently there are no effective therapeutic strategies to restore kidney homeostasis following postischemic kidney injury. In the context of ischemia-reperfusion injury, prolonged cellular hypoxia leads to energetic failure and death. However, sublethal hypoxia can trigger an adaptive response called hypoxic preconditioning. Key regulators of hypoxic responses are Hypoxia-Inducible-Factors (HIF)-1 and -2, heterodimeric basic helix-loop-helix transcription factors mostly known for their ability to regulate genes involved in angiogenesis, erythropoiesis and enhanced energy metabolism. HIF activity is negatively regulated by prolyl-hydroxylase domain proteins 1 to 3 (PHD1 to PHD3), PHD2 being the main oxygen sensor. We and others have shown that activation of HIF signaling by PHD inhibition prior to renal ischemia-reperfusion injury (IRI) evokes significant renoprotection limiting post-ischemic injury and inflammation. Using a metabolomics-based approach, we have recently identified a crucial role for the Indoleamine 2,3-dioxygenase 1 (Ido1)-Kynurenine (Kyn) axis as a mediator of the renoprotection generated by hypoxic preconditioning, but the underlying molecular mechanisms remain undefined. Identification of the mechanisms whereby hypoxic preconditioning through the Ido1-Kyn axis dictates post-ischemic kidney injury and inflammation may create novel and targeted therapeutic opportunities in the field of AKI. In this proposal, we hypothesize that PHD inactivation suppresses maladaptive post-ischemic renal inflammation and promotes kidney repair through alterations in tryptophan metabolism. To test this hypothesis, we propose three specific aims. Aim 1 examines how systemic or cell type specific IDO1-mediated changes in tryptophan metabolism affect renoprotective responses induced by PHD inhibition. Aim 2 defines whether activation of hypoxia signaling protects against ischemic kidney injury by directing reparative phenotype in kidney macrophages. Aim 3 investigates the role of tryptophan metabolic reprogramming in kidney repair in the setting of post-ischemic PHD inactivation. The proposed research is innovative because we combine functional genomics with metabolomics-based approaches to investigate the role of tryptophan metabolism in renoprotection induced by PHD inhibition. Upon conclusion, we will obtain fundamentally new insights into how PHD inactivation affects post-ischemic kidney injury and repair.