Erythropoietin

Erythropoietin is a glycoprotein hormone/cytokine that regulates the production of RBCs in the bone marrow. Erythropoietin (Epo) is produced mainly by peritubular fibroblasts in the renal cortex and to some extent in the reticuloendothelial system including the bone marrow. Liver is the main site of Epo production in the fetus.

The kidneys are the main site of the production of erythropoietin (Epo). Epo synthesis is increased by hypoxia. The Epo enhancer is activated by the hypoxia-inducible transcription factor complex HIF-1β/HIF-2α. The HIF complex binds to the hypoxia-response element (HRE) activating EPO expression. In bone marrow, Epo promotes the survival, proliferation and differentiation of erythrocytic progenitors, particularly the colony-forming units-erythroid (CFU-Es). Starting about four days after an increase in Epo levels, more reticulocytes enter the blood stream. The EPO promoter is inhibited by NF-kB which is increased in inflammation. CFU-Es express abundant Epo receptor molecules (EpoR) and undergo apoptosis in the absence of Epo. EPO can also stimulate proliferation and angiogenesis of endothelial cells that express EPO receptors. Hypoxia induces the enzyme nitric oxide synthase (NOS) in endothelial cells by increasing the production of NO.

The Epo receptor or EpoR is a membrane-spanning glycoprotein. Epo binding causes the intracellular activation of EpoR-associated Janus kinase 2 (JAK-2) which is followed by tyrosine phosphorylation. The phosphorylated EpoR provides docking sites for proteins containing SRC homology 2 (SH2) domains. This is followed by signal transduction and activation of transcription involving STAT 5, PI3 kinase and MAPK pr MAP kinase.