Erythropoietin (Epo) is a glycoprotein hormone/cytokine that regulates red blood cell (RBC) production in the bone marrow. It’s produced mainly by peritubular fibroblasts in the renal cortex and, to a lesser extent, in the reticuloendothelial system (including the bone marrow). In the fetus, the liver is the main site of Epo production.

The kidneys are the main site of erythropoietin (Epo) production, and Epo synthesis increases in response to hypoxia. The Epo enhancer is activated by the hypoxia-inducible transcription factor complex HIF-1β/HIF-2α. This HIF complex binds to the hypoxia-response element (HRE), which activates EPO expression.

In the bone marrow, Epo promotes the survival, proliferation, and differentiation of erythrocytic progenitors, especially colony-forming units-erythroid (CFU-Es). About four days after Epo levels rise, more reticulocytes enter the bloodstream. CFU-Es express abundant Epo receptor molecules (EpoR) and undergo apoptosis in the absence of Epo.

EPO promoter activity is inhibited by NF-kB, which increases during inflammation. EPO can also stimulate proliferation and angiogenesis of endothelial cells that express EPO receptors. In endothelial cells, hypoxia induces the enzyme nitric oxide synthase (NOS), increasing the production of NO.

The Epo receptor (EpoR) is a membrane-spanning glycoprotein. When Epo binds to EpoR, it activates the intracellular EpoR-associated Janus kinase 2 (JAK-2), followed by tyrosine phosphorylation. The phosphorylated EpoR then provides docking sites for proteins containing SRC homology 2 (SH2) domains. This triggers signal transduction and transcriptional activation involving STAT 5, PI3 kinase, and MAPK pr MAP kinase.