October 30, 2004
American Society of Nephrology (ASN) Renal Week 2004, St. Louis, Missouri
Abstract SA-PO672
Poster: Inflammatory, Hypoxic, and Morphogenic Mediators

J Am Soc Nephrol 15: 449A - 450A

Novel Prolyl Hydroxylase Inhibitors Overcome Inflammatory Cytokine-Mediated Suppression of EPO Secretion. Stephen Klaus, D. Gervasi, S. Spong, E. Lomongsod, M. Arend, L. Flippin, D. Liu, V. Guenzler. FibroGen, FibroGen,Inc., South San Francisco, CA.

Anemia of chronic diseases (ACD) such as rheumatoid arthritis and certain cancers is caused in part by elevated levels of circulating pro-inflammatory cytokines that suppress erythropoiesis. Pro-inflammatory cytokines such as TNF-alpha, IL-1beta and IL-6 directly inhibit erythropoietin (EPO) secretion, and further exacerbate anemia by reducing iron absorption and utilization that is necessary for hemoglobin synthesis. Hypoxia inducible factor-a (HIF-alpha) is a transcription factor that acts as the body's main sensor to low oxygen tension, and HIF responds to anemia (i.e. hypoxia) to increase erythropoiesis by elevating transcription of EPO and iron processing genes. HIF-alpha function is regulated by a family of conserved HIF prolyl hydroxylases (HIF-PH), which hydroxylate HIF-alpha and induce its degradation under normoxic conditions, but which are inhibited under hypoxia leading to HIF-alpha stabilization and activation. We developed a novel series of HIF prolyl hydroxylase inhibitors (PHI) that reversibly block HIF-PH function under normoxic conditions and which induce HIF-alpha activation and elevated levels of EPO secretion in PHI-treated cells. As expected, TNF-alpha and IL-1beta suppressed EPO secretion in a dose dependent fashion, but simultaneous or posttreatment of cells with PHI in the presence of either TNF-alpha or IL-1beta overcomes cytokine-mediated suppression of EPO secretion, with EPO induced to even higher levels than in the absence of TNF-alpha and IL-1beta. While IL-6 alone had little effect on EPO secretion, cells co-stimulated with IL-6 and PHI exhibit a synergistic increase in EPO secretion, to much higher levels than seen with PHI alone. The data indicate that PHI-mediated stabilization of HIF prevents the suppressive effects of TNF-alpha and IL-1beta on EPO production, and synergizes with IL-6 to induce even higher levels of EPO secretion. This suggests that prolyl hydroxylase inhibition may provide novel benefits in the treatment of anemias associated with chronic disease, for which available anemia therapeutics are not approved.

Scientific Advisor: FibroGen,Inc.

See also November 1, 2004 press release