November 11, 2005
American Society of Nephrology (ASN) Renal Week 2005, Philadelphia, Pennsylvania
Abstract F-PO683
Session: ESRD: Associated Anemia

Induction of Renal and Extra-Renal Erythropoietin Production by Orally Bioavailable HIF Prolyl Hydroxylase Inhibitors. Q.J. Wang, G. Guo, T. Seeley, B. Stephenson, J. Pacleb, I. Langsetmo, B. Nichols, L. Flippin, W. Ho, M. Arend, E. Turtle, D. Liu, S. Klaus. FibroGen, Inc. 225 Gateway Blvd., South San Francisco, CA 94080.

Abstract: FibroGen has developed a series of HIF prolyl hydroxylase inhibitors (PHI) that selectively induce the expression of genes that mediate erythropoiesis, including erythropoietin (EPO). Although EPO production in adults occurs primarily within the kidney, EPO is also produced constitutively and inducibly at extra-renal sites, particularly liver and brain. We determined the contribution of kidney and liver to total PHI-induced EPO levels in vivo by measurement of circulating endogenous EPO in sham operated mice and in mice receiving bilateral (total) nephrectomy (BNx). EPO mRNA expression was determined by qPCR analysis of kidney and liver derived EPO mRNA, and circulating endogenous EPO was determined in plasma by ELISA after oral administration of PHI. The results show that distinct PHI exhibited differential capacity to induce EPO after BNx in mice, suggesting that PHI-induced elevation of circulating endogenous EPO is due to differential production from renal and extra-renal sources, with different contributions from kidney and liver depending on the PHI employed. The relative proportions of EPO induced by PHI from renal and hepatic sources were generally independent of PHI dose employed. EPO expression was also examined in neural tissues by qPCR after intravenous administration of PHI, with PHI inducing both circulating and neural EPO or selective induction only in the circulation or brain. Compounds that selectively induce EPO expression in the brain may advance the development of novel neuroprotective therapeutics. The capacity of distinct PHI to differentially induce EPO from renal and hepatic tissue provides optimal flexibility in the development of therapeutic PHI to treat patients with anemia. Localized renal EPO production may maximally exploit the renoprotective properties of EPO that could slow progression to ESRD and provide cytoprotection against acute renal failure.