October 30, 2004
American Society of Nephrology (ASN) Renal Week 2004, St. Louis, Missouri
Abstract SA-PO725
Poster: Acute Renal Failure: Sepsis, Endothelium, Diagnosis

Improvement of Kidney Function in a Rat Model of Renal Ischemia-Reperfusion Injury by Treatment with a Novel HIF Prolyl Hydroxylase Inhibitor. G. Guo, A. Lin, V. Guenzler, D. Liu, S. Klaus, M. Arend, L. Flippin, C. Witschi, Q. Wang. FibroGen, FibroGen,Inc., South San Francisco, CA.

Hypoxia-inducible factor (HIF) activates the transcription of a number of renoprotective genes, including erythropoietin (EPO), vascular endothelial growth factor (VEGF), adrenomedullin, metallothionine, superoxide dismutase, and heme oxygenase-1 (HO-1), which have antioxidant, anti-apoptotic and/or antiinflammatory properties. A novel HIF-prolyl hydroxylase (HIF-PH) inhibitor, PHI, was found to stabilize HIF protein and upregulate EPO, VEGF and HO-1. Using a rat renal ischemia-reperfusion injury (IRI) model of acute renal failure (ARF), we demonstrated that a single-dose pretreatment with PHI, either orally or intravenously, protected kidney function as indicated by significant reduction in elevated blood urea nitrogen (BUN) levels. Treatment with PHI in rats also markedly elevated circulating reticulocytes in a dose-dependent fashion. Thus, in providing cell protection and/or repair, upregulation of EPO, VEGF and/or HO-1 may be one of the key mechanisms of HIF-PH inhibitor-mediated kidney protection against IRI. The tissue protective effects of HIF-PH inhibition by means of pharmacologic preconditioning may be extended to other organs suffering from IRI. Further studies are warranted to evaluate the applicability of these findings, especially in clinical ARF.

Scientific Advisor: FibroGen,Inc.

See also November 1, 2004 press release