Department of Pathology

The Evolving Role of Erythropoietin

By E. M. Kurian, M.D.

Erythropoietin (Epo) is a 165 amino acid glycoprotein which is a member of the type I cytokine family.  The main role of erythropoietin is a hypoxia-dependent regulation of  erythrocyte production and prevention of apoptosis. Epo is produced in multiple sites, with site specific angiogenic potential in the uterus and erythropoietic function in the fetal liver and adult kidney. 

Hypoxia-inducible transcription factors (HIF) induce gene expression of proteins, such as Epo, which protect tissue from oxygen and energy deprivation; and may have a specific mechanism of transport across the blood-brain-barrier to increase permeability after hypoxic events. On the 3 flanking region of the Epo gene, HIF – 1b is constitutively expressed. The HIF-1a is an oxygen labile subunit which undergoes rapid degeneration via an ubiquitin-proteosome pathway under normal conditions. In hypoxic events, HIF-1a  degradation is impaired  due to translocation from the cytoplasm into the nucleus, and heterodimerizes with HIF-1b forming a stable complex. The complex binds to the conserved 5 sequence of the hypoxia-responsive enhancer of the Epo gene upregulating transcription. Hypoglycemia, elevated intracellular calcium, and intense neuronal depolarizations generated by reactive oxygen species may also activate HIF.

Epo activates a novel pathway involving Akt (or protein kinase B) which has been shown to increase cell survival by blocking apoptosis degradation. Akt 1 and Akt 2 levels are high early in development and decrease postnatally. Akt is significant in that it is necessary for phophatidylserine (PS) residue membrane externalization to permit microglial recognition and clearance. The PS externalization may contribute to variety of diseases which include ischemic stroke, dementia, Alzheimer disease, spinal cord injury, and myocardial infarction.

The numerous sites of Epo/EpoR production and expression dictates the possibility for more than the mainstream role of erythropoietic homeostasis. The clinical applications of Epo are evolving to include treatment of anemia in chronic renal failure, anemia of prematurity, myocardial protection, critically ill patients, neuroprotective effects after stroke, and anemic oncology patients.

Conversely, there is also the potential for abuse in athletic events, which pose the following side effects of thrombosis exaggerated by dehydration, emboli, red cell aplasia, anti-epo antibodies, and hypertensive emergencies which are independent of the hematocrit level.  In regulated athletic events, detection is by Western blot differentiation of several isoforms based on isoelectric points which are a result of species and tissue-type post-translational modification. This method is expensive, difficult to interpret, and currently limited to one laboratory. 

The role of erythropoietin has developed extensively and continues to evolve with new discoveries for therapeutic use.


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Last updated on 11 September 2006 by John D. Olson, M.D., Ph.D.