HIF-Erythropoiesis
Erythropoiesis, the production of red blood cells (RBCs) in the bone marrow, is a dynamic, multi-faceted process requiring precise coordination to meet the demands of the body for oxygen. Hypoxia-inducible factor (HIF) orchestrates this process by mediating genes involved in erythropoiesis.
For example, two elements crucial to proper formation of RBCs are erythropoietin (EPO) and iron. HIF promotes EPO secretion from the kidney and other non-renal sources (e.g., liver) and up-regulates EPO receptor (EPO-R) in the bone marrow. HIF also activates factors that improve iron absorption from the gut, mobilization from storage sites, and transport to the bone marrow (e.g., transferrin, transferrin receptor, ferroportin, ceruloplasm, DMT, and DcytB).
Erythropoiesis is often suppressed in chronic inflammatory diseases due to expression of hepcidin, a regulatory hormone that limits the availability of iron for erythropoiesis even when dietary iron intake is sufficient. HIF inhibits the expression of hepcidin.
Selective activation of the erythropoietic cascade using FibroGen HIF-PHI has the potential to induce the full complement of factors necessary for erythropoiesis including EPO, EPO-R, and iron regulatory genes. HIF-PHI have also been shown to suppress inflammatory pathways, such as IL-12-mediated T helper cell production of pro-inflammatory cytokines (e.g., TNF-α and IFN-γ) and down-regulate hepcidin. Through induction of HIF-mediated erythropoiesis, HIF-PHI offer potential advantages over current anemia therapy, which is based on hormone replacement with EPO analogs and concomitant administration of intravenous iron.
