Erythropoietin (/ɪˌrɪθroʊˈpɔɪ.ɪtɪn,-rə-,-pɔɪˈɛtɪn,-ˈiːtɪn/;[1][2][3]EPO), also known aserythropoetin,haematopoietin, orhaemopoietin, is aglycoproteincytokine secreted mainly by thekidneys in response to cellularhypoxia; it stimulatesred blood cell production (erythropoiesis) in thebone marrow. Low levels of EPO (around 10 mU/mL) are constantly secreted in sufficient quantities to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO (up to 10 000 mU/mL) include anyanemia, andhypoxemia due to chronic lung disease and mouth disease.
EPO is highlyglycosylated (40% of total molecular weight), with half-life in blood around 5 h. EPO's half-life may vary between endogenous and various recombinant versions. Additional glycosylation or other alterations of EPO via recombinant technology have led to the increase of EPO's stability in blood (thus requiring less frequent injections).
Erythropoietin is an essential hormone for red blood cell production. Without it, definitiveerythropoiesis does not take place. Underhypoxic conditions, the kidney will produce and secrete erythropoietin to increase the production of red blood cells by targetingCFU-E, proerythroblast and basophilic erythroblast subsets in the differentiation. Erythropoietin has its primary effect on red blood cell progenitors and precursors (which are found in the bone marrow in humans) by promoting their survival through protecting these cells fromapoptosis, or cell death.
Erythropoietin is the primary erythropoietic factor that cooperates with various other growth factors (e.g.,IL-3,IL-6,glucocorticoids, andSCF) involved in the development oferythroid lineage frommultipotent progenitors. The burst-forming unit-erythroid (BFU-E) cells starterythropoietin receptor expression and are sensitive to erythropoietin. Subsequent stage, the colony-forming unit-erythroid (CFU-E), expresses maximal erythropoietin receptor density and is completely dependent on erythropoietin for further differentiation. Precursors of red cells, the proerythroblasts and basophilic erythroblasts also express erythropoietin receptor and are therefore affected by it.
Erythropoietin was reported to have a range of actions beyond stimulation of erythropoiesis includingvasoconstriction-dependenthypertension, stimulatingangiogenesis, and promoting cell survival via activation of EPO receptors resulting in anti-apoptotic effects on ischemic tissues. However this proposal is controversial with numerous studies showing no effect.[5] It is also inconsistent with the low levels of EPO receptors on those cells. Clinical trials in humans with ischemic heart, neural and renal tissues have not demonstrated the same benefits seen in animals. In addition some research studies have shown its neuroprotective effect on diabetic neuropathy, however these data were not confirmed in clinical trials that have been conducted on the deep peroneal, superficial peroneal, tibial and sural nerves.[6]
Erythropoietin has been shown to exert its effects bybinding to theerythropoietin receptor (EpoR).[7][8] EPO binds to the erythropoietin receptor on the red cell progenitor surface and activates aJAK2 signalling cascade. This initiates theSTAT5,PIK3 andRas MAPK pathways. This results in differentiation, survival and proliferation of the erythroid cell.[9] SOCS1, SOCS3 and CIS are also expressed which act as negative regulators of the cytokine signal.[10]
High level erythropoietin receptor expression is localized to erythroid progenitor cells. While there are reports that EPO receptors are found in a number of other tissues, such as heart, muscle, kidney and peripheral/central nervous tissue, those results are confounded by nonspecificity of reagents such as anti-EpoR antibodies.[11] In controlled experiments, a functional EPO receptor is not detected in those tissues.[12] In the bloodstream, red cells themselves do not express erythropoietin receptor, so cannot respond to EPO. However, indirect dependence of red cell longevity in the blood on plasma erythropoietin levels has been reported, a process termed neocytolysis.[13] In addition, there is conclusive evidence that EPO receptor expression is upregulated in brain injury.[14]
Erythropoietin levels in blood are quite low in the absence of anemia, at around 10 mU/mL. However, in hypoxic stress, EPO production may increase up to 1000-fold, reaching 10 000 mU/mL of blood. In adults, EPO is mainly synthesized by peritubular fibroblast-like type-1interstitial cells in the deeprenal cortex, with additional amounts being produced in the liver,[15][16][17] and thepericytes in thebrain.[18] Regulation is believed to rely on a feedback mechanism measuring blood oxygenation and iron availability.[19] Constitutively synthesized transcription factors for EPO, known ashypoxia-inducible factors, are hydroxylated and proteosomally digested in the presence of oxygen and iron. During normoxiaGATA2 inhibits the promoter region for EPO. GATA2 levels decrease during hypoxia and allow the promotion of EPO production.[20]
In 1905,Paul Carnot proposed the idea that a hormone regulates the production of red blood cells. After conducting experiments on rabbits subject tobloodletting, Carnot and his graduate studentClotilde-Camille Deflandre[25] attributed an increase in red blood cells in rabbit subjects to a hemotropic factor called hemopoietin. Eva Bonsdorff andEeva Jalavisto called the hemopoietic substance 'erythropoietin'. K.R. Reissman and Allan J. Erslev demonstrated that a certain substance, circulated in the blood, is able to stimulate red blood cell production and increasehematocrit. This substance was purified and confirmed as erythropoietin.[19][26]
In 1977, Goldwasser and Kung purified EPO.[27] Pure EPO allowed the amino acid sequence to be partially identified and the gene to be isolated.[19] Synthetic EPO was first successfully used to correct anemia in 1987.[28] In 1985, Linet al isolated the human erythropoietin gene from a genomic phage library and used it to produce EPO.[29] In 1989, the USFood and Drug Administration (FDA) approved the hormoneEpogen for use in certain anemias.[30][31]
As aperformance-enhancing drug, EPO has been banned since the early 1990s, but a first test was not available until the2000 Summer Olympics.[35] Before this test was available, some athletes were sanctioned after confessing to having used EPO, for example in theFestina affair, when a car with doping products for the Festina cycling team was found.
The first doping test in cycling was used in the2001 La Flèche Wallonne. The first rider to test positive in that race wasBo Hamburger, although he was later acquitted because his B-sample was not conclusive.[36]
A 2007 study showed that EPO has asignificant effect on exercise performance.[clarify][38] A 2017 study showed atsubmaximal exertion the effects of EPO were not distinguishable from a placebo. Stating "[At] Submaximal [exertion]...[mean power] did not differ between groups." Nevertheless, at "maximal [exertion power output was] higher in the rHuEPO group compared with the placebo group." So, even though there was no difference at lower levels of exertion atmaximal exertion the EPO groupstill performed better than the placebo group.[39]
In March 2019, American mixed martial artist and formerUFCBantamweight ChampionT.J. Dillashaw tested positive for EPO in a drug test administered byUSADA, and was stripped of the UFC bantamweight title and suspended for 2 years.[40] In September 2023 two-time tennis major championSimona Halep received a 4-year suspension by theInternational Tennis Integrity Agency for two separate violations, one concerning the level of EPO in a blood sample collected in August 2022; Halep maintained her innocence, and indicated she would appeal the ban. Halep was later cleared to return following a successful appeal, due to findings that a contaminated supplement most likely contributed to the positive tests.[41][42]
^Hosseini-Zare MS, Dashti-Khavidaki S, Mahdavi-Mazdeh M, Ahmadi F, Akrami S (July 2012). "Peripheral neuropathy response to erythropoietin in type 2 diabetic patients with mild to moderate renal failure".Clinical Neurology and Neurosurgery.114 (6):663–7.doi:10.1016/j.clineuro.2012.01.007.PMID22296650.S2CID19516031.
^Livnah O, Johnson DL, Stura EA, Farrell FX, Barbone FP, You Y, Liu KD, Goldsmith MA, He W, Krause CD, Pestka S, Jolliffe LK, Wilson IA (November 1998). "An antagonist peptide-EPO receptor complex suggests that receptor dimerization is not sufficient for activation".Nature Structural Biology.5 (11):993–1004.doi:10.1038/2965.PMID9808045.S2CID24052881.
^Hodges VM, Rainey S, Lappin TR, Maxwell AP (November 2007). "Pathophysiology of anemia and erythrocytosis".Critical Reviews in Oncology/Hematology.64 (2):139–58.doi:10.1016/j.critrevonc.2007.06.006.PMID17656101.
^Liu S, Ren J, Hong Z, Yan D, Gu G, Han G, Wang G, Ren H, Chen J, Li J (February 2013). "Efficacy of erythropoietin combined with enteral nutrition for the treatment of anemia in Crohn's disease: a prospective cohort study".Nutrition in Clinical Practice.28 (1):120–7.doi:10.1177/0884533612462744.PMID23064018.
^Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW (January 1987). "Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial".The New England Journal of Medicine.316 (2):73–8.doi:10.1056/NEJM198701083160203.PMID3537801.
^Thomsen JJ, Rentsch RL, Robach P, Calbet JA, Boushel R, Rasmussen P, Juel C, Lundby C (November 2007). "Prolonged administration of recombinant human erythropoietin increases submaximal performance more than maximal aerobic capacity".European Journal of Applied Physiology.101 (4):481–6.doi:10.1007/s00421-007-0522-8.PMID17668232.S2CID6492432.
^Heuberger JA, Rotmans JI, Gal P, Stuurman FE, van 't Westende J, Post TE, Daniels JM, Moerland M, van Veldhoven PL, de Kam ML, Ram H, de Hon O, Posthuma JJ, Burggraaf J, Cohen AF (August 2017). "Effects of erythropoietin on cycling performance of well trained cyclists: a double-blind, randomised, placebo-controlled trial".The Lancet. Haematology.4 (8):e374 –e386.doi:10.1016/S2352-3026(17)30105-9.PMID28669689.
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