UHS and UTHSCSA
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.

References:

         Fisher JW. Erythropoietin: Physiology and Pharmacology Update. Experimental Biology and Medicine 2003; 228:1-14

         Farrell F, Lee A. The Erythropoietin Receptor and Its Expression in Tumor Cells and Other Tisssues. The Oncologist. 2004; 9(suppl 5): 18-30.

         Halvorsen S, and Bechensteen AG. Physiology of erythropoietin during mammalian development. Acta Pediatr Suppl 2002; 91: 17-26.

         Brines M and Cerami A. Emerging biological roles fro erythropoietin in the nervous system. Nature Reviews Neuroscience 2005; 6: 484-494.

         Li  F, Chong ZZ, and Maiese K. Erythropoietin on a Tightrope: Balancing Neuronal and Vascular Protection between Intrinsic and Extrinsic Pathways. Neurosignals 2004; 13:265-289.

         Wallis JP. Nitric oxide and blood: a review. Transfusion Medicine 2005: (15) 1-11.

         Gore CJ, Parisotto R, Ashden MJ, Stray-Gunderson J et al. Second-generation blood tests to detect erythropoietin abuse by athletes. Journal of Hematology March 2003; 88: 333-344.

         Connes P, Caillaud C, Simar D. et al. Blood Doping: Strengths and weakness of established indirect models to detect recombinant human erythropoietin abuse on blood samples collected 48-hr post administration. Haematologica 2004; 89:891-892.

         Lasne F. Martin L, Crepin N, and deCeaurriz J. Detection of isoelectric profiles of erythropoietin in urine: differentiation of natural and administered recombinant hormones. Analytical Biochemistry. 2002; 311: 119-126.

 


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