November 17, 2006
American Society of Nephrology (ASN) Renal Week 2006, San Diego, CA
Abstract TH-PO1025

Renoprotective and Therapeutic Efficacy of the HIF Prolyl Hydroxylase Inhibitor FG-4539 in Experimental Ischemia-Reperfusion Induced Acute Kidney Injury. Q. Wang, G. Guo, R. Winmill, R. Stephenson, J. Pacleb, W Bin-Ho, L. Flippin, D. Gervasi, S. Porter, A. Lin, D. Liu, T. Seeley, S. Klaus.

FibroGen, Inc. 225 Gateway Blvd., SSF, CA 94080.

Abstract: Previous studies demonstrate that hypoxic preconditioning or pretreatment with small molecule Hypoxia Inducible Factor (HIF) prolyl hydroxylase inhibitors (PHI) mitigates renal ischemia-reperfusion injury (IRI) and subsequent acute kidney injury (AKI), leading to significant cytoprotection and preservation of renal function (Guo et al., ASN 2004). FG-4539 is a novel small molecule HIF PHI that can be administered either orally or intravenously and that is under clinical development to treat ischemic disease including ischemic AKI, and which exhibits potent renoprotective, cardioprotective and neuroprotective efficacy (Langsetmo et al., Stroke 37, 2006). We extend our results in preclinical ischemic AKI models and demonstrate here that FG-4539 exhibits potent dose-dependent renoprotective efficacy in both mouse and rat, leading to significant preservation of renal function. Proteomic and genomic analyses show that FG-4539 preconditioning synergizes with ischemic stress to promote endogenous erythropoietin (Epo) production, but broadly limits the induction of pro-inflammatory and pro-apoptotic genes in response to renal IRI. FG-4539 also mitigates the onset of anemia induced by renal failure, in part by elevation of endogenous Epo. The therapeutic potential of FG-4539 was confirmed in a rat model of renal IRI by administering FG-4539 either at the time of reperfusion or at delayed times post-IRI. The results demonstrate that activation of HIF by small molecule prolyl hydroxylase inhibitors and their renoprotective efficacy is not limited to prophylactic preconditioning regimens, and that FG-4539 can be administered therapeutically hours after the onset of IRI-mediated injury.

See also November 17, 2006 press release