Erythropoietin (EPO) maintains the mass of red blood cells by promoting the survival, proliferation and differentiation of erythrocytic progenitors in the bone marrow. The present article summarizes molecular and systemic mechanisms in EPÓs control of erythropoiesis. Circulating EPO originates mainly from fibroblasts in the renal cortex. EPO production is controlled at the transcriptional level. GATA-2 blocks the EPO-promoter in normoxia, but is removed in hypoxia. Even more important is the regulation by the heterodimeric (α/β) hypoxia-inducible transcription factors (HIFs). HIF- subunits are inactivated in normoxia involving three HIF- prolyl hydroxylases (PHD-1, -2 and -3), which initiate the proteasomal degradation of HIF-α, and an asparaginyl hydroxylase, which prevents trans-activation. In hypoxia, the HIF- / complexes stimulate the EPO enhancer. The HIF-α hydroxylases contain Fe2+, and they use -ketoglutarate as co-factor. Small molecule inhibitors of the HIF- hydroxylases (HIF-stabilizers) have been described, which are effective orally. The in vivo EPO response on hypoxic stress is dynamic, i.e., the concentration of circulating EPO rises initially sharply and then declines despite persisting O2 deficiency. Physical work (sport) has no major direct influence on EPO production. Overall, humoral mediators play a minor role; most likely thyroid hormones (T3/T4) are stimulators. EPO and angiotensin II cooperate in the maintenance of the blood volume. EPO overproduction leads to erythrocytosis. EPO deficiency causes anemia, such as in chronic kidney disease. Here, recombinant EPO can be of use.
Research Areas and Centers
- Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)