Advanced chronic kidney disease (CKD) and end stage renal disease (ESRD) are characterized by the inability of the diseased kidney to respond to hypoxia with adequate production of erythropoietin (EPO), the glycoprotein hormone that is essential for the generation of red blood cells, and is furthermore associated with absolute and functional iron deficiency. This leads to the development of anemia, a clinical hallmark of advanced CKD, which is typically treated with recombinant human EPO and intravenous iron preparations. The use of recombinant EPO not only represents a major cost factor in the care of patients with advanced CKD and ESRD, but also is associated with significant cardiovascular risks prompting the FDA to issue several black box warnings. While recombinant human EPO has been in use for over 25 years, the pathogenesis of renal anemia is poorly understood. The long-term goals of this research project are to understand the cellular and molecular mechanisms that underlie the pathogenesis of renal anemia. A key pathway in the oxygen-dependent regulation of renal EPO is the prolyl-4-hydroxylase (PHD) / hypoxia-inducible factor (HIF) pathway. Over the last 10 years our laboratory and others have demonstrated that HIF-2 regulates the hypoxic induction of EPO in kidney and liver. The pathogenesis of renal anemia is intricately linked to renal fibrogenesis, as perivascular interstitial cells and pericytes are not only the cellular sources of EPO in the kidney but also give rise to collagen-producing myofibroblasts. To understand the regulation of renal EPO production in CKD on a cellular and molecular level unique genetic and pharmacologic tools are used to dissect the PHD/HIF/EPO axis in normal and in injured kidneys. Under this grant we hypothesize that the PHD/HIF oxygen sensing system in conjunction with iron responsive element binding protein (IRP) plays a critical role in regulating the differentiation state of EPO- producing perivascular interstitial cells and pericytes. We propose that abnormal HIF-2 regulation generates specific signals that modulate cell differentiation and function and thus has a crucial role in the pathogenesis of renal anemia. Our studies aim at a) elucidating the role of the perivascular PHD/HIF-2 axis in anemia development under renal injury conditions, b) at characterizing molecular phenotype that associates with EPO-producing cells taking advantage of single cell RNA sequencing technology and c) at investigating the role of IRP1 in the regulation of HIF-2 activity in renal interstitial cells and EPO production under baseline and kidney injury conditions.
Advanced chronic kidney disease represents a major cause of morbidity and mortality for our Veterans and is frequently associated with anemia, the inability of the body to produce adequate numbers of red blood cells. This grant investigates the cellular, molecular and metabolic mechanisms that underlie the regulation of erythropoietin, the hormone that is made by the kidney and is essential for red blood cell production. Work proposed under this grant will further our understanding of the causes of anemia associated with kidney failure. This project has high potential for the development of novel therapies that improve anemia management in patients who are on dialysis.
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