Erythropoietin (EPO) is a 34 kDa glycoprotein hormone in the type I cytokine family and is related to thrombopoietin [1]. Its three N-glycosylation sites, four alpha helices, and N- to C-terminal disulfide bond are conserved across species [2, 3]. Glycosylation of EPO is required for biological activities in vivo [4]. Mature mouse EPO shares 95% amino acid sequence identity with rat EPO and 73%-82% with bovine, canine, equine, feline, human, ovine, and porcine EPO. Epo is primarily produced in the kidney by a population of fibroblast-like cortical interstitial cells adjacent to the proximal tubules [5]. It is also produced in much lower, but functionally significant amounts by fetal hepatocytes and in adult liver and brain [6-8]. EPO promotes erythrocyte formation by preventing the apoptosis of early erythroid precursors which express the (EPO receptor (EPOR))[8, 9]. EPO R has also been described in brain, retina, heart, skeletal muscle, kidney, endothelial cells, and a variety of tumor cells [7,8,10,11]. Ligand induced dimerization of EPOR triggers JAK2-mediated signaling pathways followed by receptor/ligand endocytosis and degradation [1,12]. Rapid regulation of circulating EPO allows tight control of erythrocyte production and hemoglobin concentrations. Anemia or other causes of low tissue oxygen tension induce EPO production by stabilizing the hypoxia-induceable transcription factors HIF-1 alpha and HIF-2 alpha [1,6]. EPO additionally plays a tissue-protective role in ischemia by blocking apoptosis and inducing angiogenesis [7,8,13].
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