Considering that the primary function of red cells is the carriage and delivery of oxygen, it is not surprising that the regulation of red cell production is tightly controlled by cellular oxygen sensing. The cellular response to hypoxia was described through the Nobel prize winning works of Kaelin, Ratcliffe and Semenza.
Erythropoietin (EPO) is a hormone that is produced by fibroblast-like cells found in the renal cortex mainly at the juxta-medullary junction and outer medulla, in close association with the peritubular capillaries and proximal convoluted tubule. These cells sense fluctuations in tissue oxygen and regulate the release of EPO, which stimulates erythropoiesis in the marrow.
Transcription of the EPO gene is enhanced in the hypoxic state by the transcription factor hypoxia-inducible factor (HIF) that binds to the hypoxia-response elements (HRE) adjacent to the gene. In addition to EPO, HIF also upregulates the transcription of hundreds of other genes that play a role in hypoxia response and erythropoiesis. This includes various genes responsible for iron absorption and metabolism.
HIF is a constitutively produced protein. In normoxic states when tissue oxygen is adequate, the produced HIF is destroyed by ubiquitination following hydroxylation of its proline residues by action of the prolyl-hydroxylase domain proteins (PHD). However, in hypoxic states proline hydroxylation by PHD is interrupted and therefore HIF escapes ubiquitination and proteosomal degradation. The accumulated HIF can then translocate to the nucleus and bind to the HRE of various genes including EPO and increase its release.
Various erythropoiesis stimulating agents (ESA) and inhibitors of prolyl-hydroxylase are now in use or in development for the treatment of anaemia.
Blood & Water 