Our long-term goal is to understand the pathogenesis of renal anemia and to develop new and safe therapies for its treatment. Anemia is a classic manifestation of advanced chronic kidney disease (CKD) and results from the diminished ability of the diseased kidney to produce adequate amounts of erythropoietin (EPO), the glycoprotein hormone that is essential for red blood production. Anemia associated with CKD or end stage renal disease (ESRD) is typically treated with recombinant EPO. The use of recombinant EPO not only represents a major cost factor in the care of patients with advanced CKD and ESRD, but also has raised significant cardiovascular safety concerns, which prompted the FDA to issue several black box warnings. While the administration of recombinant EPO to renal patients has been a hallmark of supportive care in Nephrology for more than 20 years, the molecular mechanisms that underlie the pathogenesis of renal anemia are surprisingly poorly understood. A key pathway in the regulation of renal EPO production is the hypoxia-inducible factor (HIF) pathway. Although the hypoxic induction of EPO serves as a paradigm for hypoxic gene regulation, the regulation of renal EPO synthesis under renal injury conditions is incompletely understood on both, the cellular and the molecular level. Over the last 5 years our laboratory and other groups have demonstrated that HIF-2 regulates the hypoxic induction of EPO in the kidney and liver, and that the HIF pathway can be pharmacologically targeted to treat patients with anemia. To understand the regulation of renal EPO production on a cellular and molecular level we have begun to use genetic and pharmacologic approaches to dissect the HIF/EPO axis in normal and in injured kidneys. Under this grant, we hypothesize that HIF-2 controls renal EPO production by regulating renal interstitial cell plasticity. We use genetically engineered mice to a) define the cell types in the kidney that have EPO-producing ability, b) to determine their contribution in the regulation of erythropoiesis at baseline and under hypoxic stress conditions, c) to characterize the role of the three major HIF prolyl-hydroxylases in the regulation of renal interstitial hypoxia responses and d) to examine HIF-2 function under renal injury conditions.

Public Health Relevance

End stage renal disease represents a major cause of morbidity and mortality for our Veterans. Anemia, the inability of the body to produce enough red blood cells, is a hallmark of end stage renal disease. This grant investigates cellular and molecular mechanisms that underlie the regulation of erythropoietin, the hormone that is made by the kidney to produce red blood cells. Work proposed here 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 and who suffer from other causes of anemia.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Nephrology (NEPH)
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Veterans Health Administration
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Haase, Volker H (2017) HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism. Hemodial Int 21 Suppl 1:S110-S124
Kobayashi, Hanako; Liu, Jiao; Urrutia, Andres A et al. (2017) Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development. Kidney Int 92:1370-1383
Haase, Volker H (2017) Therapeutic targeting of the HIF oxygen-sensing pathway: Lessons learned from clinical studies. Exp Cell Res 356:160-165
Kobayashi, Hanako; Liu, Qingdu; Binns, Thomas C et al. (2016) Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin. J Clin Invest 126:1926-38
Cho, Sung Hoon; Raybuck, Ariel L; Stengel, Kristy et al. (2016) Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system. Nature 537:234-238
Kapitsinou, Pinelopi P; Rajendran, Ganeshkumar; Astleford, Lindsay et al. (2016) The Endothelial Prolyl-4-Hydroxylase Domain 2/Hypoxia-Inducible Factor 2 Axis Regulates Pulmonary Artery Pressure in Mice. Mol Cell Biol 36:1584-94
Urrutia, Andres A; Afzal, Aqeela; Nelson, Jacob et al. (2016) Prolyl-4-hydroxylase 2 and 3 coregulate murine erythropoietin in brain pericytes. Blood 128:2550-2560
Farsijani, Navid M; Liu, Qingdu; Kobayashi, Hanako et al. (2016) Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin. J Clin Invest 126:1425-37
Koury, Mark J; Haase, Volker H (2015) Anaemia in kidney disease: harnessing hypoxia responses for therapy. Nat Rev Nephrol 11:394-410
Haase, Volker H (2015) A breath of fresh air for diabetic nephropathy. J Am Soc Nephrol 26:239-41

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