Regulation of erythropoietin production

Abstract

The hormone erythropoietin (Epo) maintains red blood cell mass by promoting the survival, proliferation and differentiation of erythrocytic progenitors. Circulating Epo originates mainly from fibroblasts in the renal cortex. Epo production is controlled at the transcriptional level. Hypoxia attenuates the inhibition of the Epo promoter by GATA-2. More importantly, hypoxia promotes the availability of heterodimeric (α/β) hypoxia-inducible transcription factors (predominantly HIF-2) which stimulate the Epo enhancer. The HIFs are inactivated in normoxia by enzymatic hydroxylation of their α-subunits. Three HIF-α prolyl hydroxylases (PHD-1, -2 and -3) initiate proteasomal degradation of HIF-α, while an asparaginyl hydroxylase ('factor inhibiting HIF-1', FIH-1) inhibits the transactivation potential. The HIF-α hydroxylases contain Fe(2+) and require 2-oxoglutarate as co-factor. The in vivo response is dynamic, i.e. the concentration of circulating Epo increases initially greatly following an anaemic or hypoxaemic stimulus and then declines despite continued hypoxia. Epo and angiotensin II collaborate in the maintenance of the blood volume. Whether extra-renal sites (brain, skin) modulate renal Epo production is a matter of debate. Epo overproduction results in erythrocytosis. Epo deficiency is the primary cause of the anaemia in chronic kidney disease and a contributing factor in the anaemias of chronic inflammation and cancer. Here, recombinant analogues can substitute for the hormone.

Figure 1. Diagram of the feedback regulation of erythropoiesis

Lack of O₂ (hypoxia) is a stimulus for the synthesis of erythropoietin (Epo), primarily in the kidneys. Epo is a survival, proliferation and differention factor for the erythrocytic progenitors, particularly the colony-forming units-erythroid (CFU-Es). The O₂ capacity of the blood increases with the enhanced release of reticulocytes. The role of extra-renal sites (brain, skin) in the control of the renal Epo synthesis is still incompletely understood. BFU-E, burst-forming unit-erythroid.