A glycoprotein cytokine: Erythropoietin

Description

Erythropoietin (EPO) is a 165 amino acid glycoprotein. Several well-established studies have shown that in adults, the kidney is the main source of the circulating EPO, where this hormone is responsible for maintaining the red blood cell mass. The kidney cells that make erythropoietin are sensitive to low oxygen levels in the blood that travel through the kidney. These cells make and release erythropoietin when the oxygen level is too low. A low oxygen level may indicate a diminished number of red blood cells (anemia) or hemoglobin molecules that carry oxygen through the body.

Biological function

Erythropoietin (EPO) is the main regulator of red blood cell production. EPO prevents programmed cell death (apoptosis) of erythrocyte precursors. However, studies unexpectedly observed that the EPO receptor (EPOR) was expressed by endothelial cells and within the central nervous system (CNS). Besides erythropoiesis, EPO also acts as an important neurotrophic molecule in brain development. After brain injury, the levels of EPO have been shown to increase in the brain, where it functions as a neuroprotectant. Moreover, it was shown that astrocytes possess the capacity for producing and secreting EPO[1]. Finally, EPORs were found on other organs, such as the heart, placenta, adipose tissue, and skin. It has been shown that many tissues locally produce and release EPO in response to hypoxic, biochemical, and physical stress. EPO protects tissues from ischemia and reperfusion injury, has anti-apoptosis effects, and improves regeneration after injury. On the other hand, cellular and animal studies have shown that EPO is a paracrine-autocrine tissue-protective molecule. Metabolic stress triggers apoptosis in tissue as an adaptive response to limit the spread of infection by destroying surrounding tissue[2]. This immune response is essential to limit infection, but excessive apoptosis causes more damage within the region immediately surrounding the injured area. EPO is an antagonist of this biological process, and EPO also antagonizes pro-inflammatory cytokine activity and promotes healing following injury.

Uses

Erythropoietin available for use as therapeutic agents are produced by recombinant DNA technology in cell culture, and include Epogen/Procrit (epoetin alfa) and Aranesp (darbepoetin alfa); they are used in treating anemia resulting from chronic kidney disease, chemotherapy-induced anemia in patients with cancer, inflammatory bowel disease (Crohn's disease and ulcerative colitis) and myelodysplasia from the treatment of cancer (chemotherapy and radiation). The package inserts include boxed warnings of increased risk of death, myocardial infarction, stroke, venous thromboembolism, and tumor recurrence, particularly when used to increase the hemoglobin levels to more than 11 g/dL to 12 g/dL.    

Adverse effects

However, research has found that EPO robustly induces erythropoiesis and elevates red blood cell counts. Chronic administration is therefore likely to increase blood viscosity and produce adverse effects in non-anemic populations. 

References

[1] Tiwari N, et al. A Comparative Analysis of Erythropoietin and Carbamoylated Erythropoietin Proteome Profiles. Life, 2021; 11: 359.

[2] Nekoui A, et al. Erythropoietin and Nonhematopoietic Effects. The American Journal of the Medical Sciences, 2017; 9: 285–290.