Acute kidney injury (AKI) resulting from ischemia-reperfusion injury (IRI) is a frequently encountered clinical problem and associates with high mortality in a critical care setting. It is furthermore an important contributor to the progressionof chronic kidney disease (CKD). A central pathway in the regulation of renal hypoxia/ischemia responses is the prolyl-hydroxylase (PHD)/hypoxia-inducible factor (HIF) oxygen-sensing pathway. PHD proteins are iron- and 2-oxoglutarate-dependent oxygenases that function as oxygen sensors and regulate HIF activity by catalyzing the hydroxylation of specific proline residues within the oxygen-dependent degradation domain of it's alpha-subunit. HIFs are pleiotropic heterodimeric transcription factors that play key roles in cellular adaptation and survival under hypoxic/ischemic conditions. All three main HIF-PHDs, PHD1, -2 and -3, are expressed in the kidney. While PHD2 regulates HIF-1 activity in renal epithelial cells and has been shown to control erythropoietin production in renal interstitial cells, the role of PHD1 and PHD3 in renal hypoxia responses and pathophysiology is unknown. Our laboratory and other groups have demonstrated in preclinical animal models that short-term pharmacologic inactivation of renal PHDs has great therapeutic potential for the prevention of acute ischemic injuries and their long-term sequelae. In order to understand the functional role of individual PHDs in renal physiology and to gain insight into the molecular and cellular basis of PHD/HIF-mediated renoprotection, we have begun to use genetic and pharmacologic approaches to dissect cell type-specific PHD functions and their role in the regulation of renal metabolism. Here we hypothesize that PHD/HIF-controlled re-programming of metabolism in renal epithelial cells plays a central role in determining the biological outcome of ischemic kidney injuries. Under this grant we use genetically engineered mice to investigate the metabolic consequences of acute PHD inactivation in the kidney.
Three specific aims are proposed.
Aims 1 investigates the role of PHD2 in renal energy metabolism, aim 2 examines the functional role of tubular epithelial PHD1 and PHD3 in renal physiology and IRI, and aim 3 examines specific metabolic pathways that associate with cytoprotection in IRI.
This grant investigates the role of HIF prolyl-hydroxylation in acute ischemic kidney injury. Work proposed under this grant will further our understanding of the molecular mechanism that lead to protection from acute kidney injury with a specific emphasis on renal metabolism. Because of its central role in renal hypoxia responses, pharmacologic targeting of the PHD/HIF axis has great potential to improve the clinical outcome of ischemic kidney injuries.