Erythropoietin functions in a classic negative feedback loop whereby increased synthesis in the kidney as a consequence of reduced oxygen delivery stimulates the release of mature RBCs into the bloodstream via interaction of the hormone with a response on RBC progenitor cells. Erythropoietin is produced in the kidney by cortical peritubular interstitial fibroblasts that increase synthesis of hormone in response to hypoxia. Under normal, basal conditions, the serum erythropoietin concentration is in the range of 0.01-0.003 U/ Ml. The circulating erythropoietin level typically increases 100 to 1000 fold in response to anemia and hypoxia in individuals with kidney disease. Regulation of erythropoietin synthesis by the peritubular fibroblasts is mediated primarily through binding of the transcription factor hypoxia-inducible factor (HIF), a dimer compromised of HIF-1? and HIF B subunits, to a hypoxia response element in erythropoietin gene and other related hypoxia-responsive genes, increasing their transcription. In the presence of hypoxia, HIF degradation is impaired and the transcription complex enhances transcription of the erythropoietin gene with subsequent translation and secretion of the hormone (Kimmel & Rosenberg, 2015). Normal basal erythropoiesis and the ability to increase RBC production in response to hypoxia and anemia are also being stimulated. However, adequate and enough nutrients are necessary for this process, such as supplies of iron, vitamin B12, and folate.
Chronic anemia-induced hypoxia triggers regulatory pathways that mediate long-term adaptive cardiac and cerebral changes, mainly at the transcriptional level. These adaptive mechanisms include a regulated cerebral blood flow and cardiac output, angiogenesis and cytoprotection triggered by hypoxia-inducible factor 1 alpha (HIF-1?), vascular endothelial growth factor (VEGF), neuronal nitric oxide synthase (nNOS) and Epo pathways. All these compensatory mechanisms purpose to improve oxygen delivery and to protect the brain and heart from hypoxic injury. Functional cardiac adaptations such as cardiac hypertrophy, increased cardiac output as well as, angiogenesis occurred along with the activation of HIF1?/VEGF and Epo/EpoR pathways under chronic anemia and hypoxia (Swenson & Bartsch, 2013).
References:
American Society of Hematology, 2010. http://www.hematology.org/patients/blood-disorders
/anemia/5225.aspx.
Ciccone,2013. Davis’s drug guide for rehabilitation professionals.
Braunstein. Merck Manual. https:www.merckmanuals.com/home/blood.disorders/anemia/overview-
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Kimmel ; Rosenberg, 2015. Chronic Renal Disease. ISBN-13:978-0124116023
Nabili,2017. Anemia. Emedicinehealth.

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