Erythropoietin

Erythropoietin (EPO) is a glycoprotein hormone (167 amino acids) released from the kidneys in response to hypoxia. The fetal liver and kidneys are major sites for the production of EPO.

17.2.1 Mechanism of Synthesis

Hypoxic inducible factor (HIF) is a transcriptional factor regulating the erythropoietin gene expression. It is a heterodimer made of HIF-α (HIF-1a/HIF-2a/HIF-3a) and HIF-1β subunits. Under normoxic conditions, HIF-1α will be hydroxylated by oxygen-sensitive hydroxylases such as prolyl hydroxylase (PHD) and factor inhibiting HIF (FIH). Further, the hydroxylated HIF-1α will undergo ubiquitination and proteasome degradation. During cellular hypoxia, the reduced activity of oxygen-sensitive hydroxylases leads to a reduction in the degradation of HIF-1α and stabilization of HIFα. The stabilized HIFα binds to a specific region in the genome known as the hypoxia-response element (HRE) to increase the transcription of the EPO gene.

17.2.3 Biological Effects

EPO is essential for the survivability of erythrocyte progeni­tor cells and their subsequent differentiation to colony­forming unit-erythrocyte (CFU-E) cells. It results in the swift passage of erythroblasts through different stages in erythropoiesis, thereby increasing the rate of erythropoiesis (Fig. 17.2). Apart from the erythrocyte progenitors, EPO is found to have angiogenic effects on the endothelial cells and neurotrophic effects in the brain and regulate bone mass and formation of skeletal muscle fibers.

17.2.4 Regulation of Secretion

Hypoxia is by far the potent stimulus for EPO secretion, with 90% of EPO formed in kidneys and the rest from the liver, brain, spleen, and lungs.

Know More...

• Since EPO is heavily glycosylated, it has a long circulatory half-life of 1 day.

• EPO increases the rate of erythropoiesis as high as ten times.

• Effects of EPO on erythrocyte numbers can only be seen after 5 days (time taken for erythropoiesis).

17.3