Protein that stimulates red blood cell production
Erythropoietin
(
;
[1]
[2]
[3]
EPO
), also known as
erythropoetin
,
haematopoietin
, or
haemopoietin
, is a
glycoprotein
cytokine
secreted mainly by the
kidneys
in response to cellular
hypoxia
; it stimulates
red blood cell
production (
erythropoiesis
) in the
bone 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 any
anemia
, and
hypoxemia
due to chronic lung disease and mouth disease.
Erythropoietin is produced by interstitial
fibroblasts
in the kidney in close association with the
peritubular capillary
and
proximal convoluted tubule
. It is also produced in
perisinusoidal
cells in the
liver
. Liver production predominates in the fetal and perinatal period; renal production predominates in adulthood. It is homologous with
thrombopoietin
.
Exogenous
erythropoietin, recombinant human erythropoietin (rhEPO), is produced by
recombinant DNA technology
in
cell culture
and are collectively called
erythropoiesis-stimulating agents
(ESA): two examples are
epoetin alfa
and
epoetin beta
. ESAs are used in the treatment of
anemia
in
chronic kidney disease
, anemia in
myelodysplasia
, and in anemia from
cancer
chemotherapy
. Risks of therapy include death,
myocardial infarction
,
stroke
,
venous thromboembolism
, and tumor recurrence. Risk increases when EPO treatment raises hemoglobin levels over 11 g/dL to 12 g/dL: this is to be avoided.
rhEPO has been used illicitly as a
performance-enhancing drug
.
[4]
It can often be detected in blood, due to slight differences from the endogenous protein; for example, in features of
posttranslational modification
.
Pharmacology
[
edit
]
EPO is highly
glycosylated
(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).
Function
[
edit
]
Red blood cell production
[
edit
]
Erythropoietin is an essential hormone for red blood cell production. Without it, definitive
erythropoiesis
does not take place. Under
hypoxic
conditions, the kidney will produce and secrete erythropoietin to increase the production of red blood cells by targeting
CFU-E
, pro
erythroblast
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 from
apoptosis
, or cell death.
Erythropoietin is the primary erythropoietic factor that cooperates with various other growth factors (e.g.,
IL-3
,
IL-6
,
glucocorticoids
, and
SCF
) involved in the development of
erythroid
lineage from
multipotent progenitors
. The burst-forming unit-erythroid (
BFU-E
) cells start
erythropoietin 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.
Nonhematopoietic roles
[
edit
]
Erythropoietin was reported to have a range of actions beyond stimulation of erythropoiesis including
vasoconstriction
-dependent
hypertension
, stimulating
angiogenesis
, 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]
Mechanism of action
[
edit
]
Erythropoietin has been shown to exert its effects by
binding
to the
erythropoietin receptor
(EpoR).
[7]
[8]
EPO binds to the erythropoietin receptor on the red cell progenitor surface and activates a
JAK2
signalling cascade. This initiates the
STAT5
,
PIK3
and
Ras 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]
Synthesis and regulation
[
edit
]
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 synthesized mainly by interstitial cells in the peritubular capillary bed of the
renal cortex
, with additional amounts being produced in the liver,
[15]
[16]
[17]
and the
pericytes
in the
brain
.
[18]
Regulation is believed to rely on a feedback mechanism measuring blood oxygenation and iron availability.
[19]
Constitutively synthesized transcription factors for EPO, known as
hypoxia-inducible factors
, are hydroxylated and proteosomally digested in the presence of oxygen and iron. During normoxia
GATA2
inhibits the promoter region for EPO. GATA2 levels decrease during hypoxia and allow the promotion of EPO production.
[20]
Erythropoietin production can be induced by
HIF-2α
as well as by
PGC-1α
.
[21]
Erythropoietin also activates these factors, resulting in a
positive feedback loop
.
[21]
Medical use
[
edit
]
Erythropoietins 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
,
[22]
chemotherapy induced anemia in patients with cancer,
inflammatory bowel disease
(
Crohn's disease
and
ulcerative colitis
)
[23]
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.
[24]
History
[
edit
]
In 1905,
Paul Carnot
proposed the idea that a hormone regulates the production of red blood cells. After conducting experiments on rabbits subject to
bloodletting
, Carnot and his graduate student
Clotilde-Camille Deflandre
[25]
attributed an increase in red blood cells in rabbit subjects to a hemotropic factor called hemopoietin. Eva Bonsdorff and
Eeva 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 increase
hematocrit
. 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, Lin
et al
isolated the human erythropoietin gene from a genomic phage library and used it to produce EPO.
[29]
In 1989, the US
Food and Drug Administration
(FDA) approved the hormone
Epogen
for use in certain anemias.
[30]
[31]
Gregg L. Semenza
and
Peter J. Ratcliffe
studied the EPO gene and its oxygen-dependent regulation. Along with
William Kaelin Jr.
, they were awarded the 2019
Nobel Prize in Physiology or Medicine
for their discovery of
hypoxia-inducible factor
(HIF), which regulates the EPO gene, as well as other genes, in response to hypoxia.
[32]
Biosimilars
[
edit
]
In December 2007, Retacrit and Silapo (both
epoetin zeta
) were approved for use in the European Union.
[33]
[34]
Usage as doping product
[
edit
]
As a
performance-enhancing drug
, EPO has been banned since the early 1990s, but a first test was not available until the
2000 Summer Olympics
.
[35]
Before this test was available, some athletes were sanctioned after confessing to having used EPO, for example in the
Festina affair
, when a car with doping products for the Festina cycling team was found.
The first doping test in cycling was used in the
2001 La Fleche Wallonne
. The first rider to test positive in that race was
Bo Hamburger
, although he was later acquitted because his B-sample was not conclusive.
[36]
The
U.S. Postal Service Pro Cycling Team
, under the leadership of
Lance Armstrong
and
Johan Bruyneel
, ran a sophisticated doping program that lasted for many years during the late 1990s and early 2000s. Erythropoietin was a common substance used by the cyclists.
[37]
A 2007 study showed that EPO has a
significant effect on exercise performance.
[
clarify
]
[38]
A 2017 study showed at
submaximal
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 at
maximal
exertion the EPO group
still
performed better than the placebo group.
[39]
In March 2019, American mixed martial artist and former
UFC
Bantamweight Champion
T.J. Dillashaw
tested positive for EPO in a drug test administered by
USADA
, and was stripped of the UFC bantamweight title and suspended for 2 years.
[40]
In September 2023 two-time tennis major champion
Simona Halep
received a 4-year suspension by the
International 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.
[41]
EPO has been used as a performance enhancing agent in
horse racing
since at least 2019.
[42]
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Further reading
[
edit
]
- Liu C, Huang C, Xie J, Li H, Hong M, Chen X, Wang J, Wang J, Li Z, Wang J, Wang W (October 2020).
"Potential Efficacy of Erythropoietin on Reducing the Risk of Mortality in Patients with Traumatic Brain Injury: A Systematic Review and Meta-Analysis"
.
Biomed Res Int
.
2020
: 7563868.
doi
:
10.1155/2020/7563868
.
PMC
7644316
.
PMID
33178833
.
- Takeuchi M, Kobata A (September 1991). "Structures and functional roles of the sugar chains of human erythropoietins".
Glycobiology
.
1
(4): 337?46.
doi
:
10.1093/glycob/1.4.337
.
PMID
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.
- Semba RD, Juul SE (August 2002). "Erythropoietin in human milk: physiology and role in infant health".
Journal of Human Lactation
.
18
(3): 252?61.
doi
:
10.1177/089033440201800307
.
PMID
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.
S2CID
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.
- Ratcliffe PJ (2002).
"From erythropoietin to oxygen: hypoxia-inducible factor hydroxylases and the hypoxia signal pathway"
.
Blood Purification
.
20
(5): 445?50.
doi
:
10.1159/000065201
.
PMID
12207089
.
S2CID
46866485
.
- Westenfelder C (2002). "Unexpected renal actions of erythropoietin".
Experimental Nephrology
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:
10.1159/000065304
.
PMID
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.
S2CID
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.
- Becerra SP, Amaral J (December 2002). "Erythropoietin--an endogenous retinal survival factor".
The New England Journal of Medicine
.
347
(24): 1968?70.
doi
:
10.1056/NEJMcibr022629
.
PMID
12477950
.
- Genc S, Koroglu TF, Genc K (March 2004). "Erythropoietin and the nervous system".
Brain Research
.
1000
(1?2): 19?31.
doi
:
10.1016/j.brainres.2003.12.037
.
PMID
15053948
.
S2CID
46246546
.
- Fandrey J (June 2004). "Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression".
American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
.
286
(6): R977?88.
doi
:
10.1152/ajpregu.00577.2003
.
PMID
15142852
.
S2CID
697196
.
- Juul S (March 2004). "Recombinant erythropoietin as a neuroprotective treatment: in vitro and in vivo models".
Clinics in Perinatology
.
31
(1): 129?42.
doi
:
10.1016/j.clp.2004.03.004
.
PMID
15183662
.
- Buemi M, Caccamo C, Nostro L, Cavallaro E, Floccari F, Grasso G (March 2005). "Brain and cancer: the protective role of erythropoietin".
Medicinal Research Reviews
.
25
(2): 245?59.
doi
:
10.1002/med.20012
.
PMID
15389732
.
S2CID
46380760
.
- Sytkowski AJ (July 2007). "Does erythropoietin have a dark side? Epo signaling and cancer cells".
Science's STKE
.
2007
(395): pe38.
doi
:
10.1126/stke.3952007pe38
.
PMID
17636183
.
S2CID
43566459
.
External links
[
edit
]
- "Erythropoietin"
.
Drug Information Portal
. U.S. National Library of Medicine.
- Overview of all the structural information available in the
PDB
for
UniProt
:
P01588
(Erythropoietin) at the
PDBe-KB
.
Articles and topics related to Erythropoietin
|
---|
PDB gallery
|
---|
-
1buy
: HUMAN ERYTHROPOIETIN, NMR MINIMIZED AVERAGE STRUCTURE
-
1cn4
: ERYTHROPOIETIN COMPLEXED WITH EXTRACELLULAR DOMAINS OF ERYTHROPOIETIN RECEPTOR
-
1eer
: CRYSTAL STRUCTURE OF HUMAN ERYTHROPOIETIN COMPLEXED TO ITS RECEPTOR AT 1.9 ANGSTROMS
|
|
---|
Angiopoietin
| |
---|
CNTF
| |
---|
EGF (ErbB)
| |
---|
FGF
| FGFR1
| |
---|
FGFR2
|
- Agonists:
Ersofermin
- FGF
(
1
,
2 (bFGF)
,
3
,
4
,
5
,
6
,
7
(
KGF
),
8
,
9
,
10 (KGF2)
,
17
,
18
,
22
)
- Palifermin
- Repifermin
- Selpercatinib
- Sprifermin
- Trafermin
|
---|
FGFR3
| |
---|
FGFR4
| |
---|
Unsorted
| |
---|
|
---|
HGF (c-Met)
| |
---|
IGF
| |
---|
LNGF (p75
NTR
)
| |
---|
PDGF
| |
---|
RET (GFL)
| |
---|
SCF (c-Kit)
| |
---|
TGFβ
| |
---|
Trk
| TrkA
|
- Negative allosteric modulators:
VM-902A
|
---|
TrkB
|
- Agonists:
3,7-DHF
- 3,7,8,2'-THF
- 4'-DMA-7,8-DHF
- 7,3'-DHF
- 7,8-DHF
- 7,8,2'-THF
- 7,8,3'-THF
- Amitriptyline
- BDNF
- BNN-20
- Deoxygedunin
- Deprenyl
- Diosmetin
- DMAQ-B1
- HIOC
- LM22A-4
- N-Acetylserotonin
- NT-3
- NT-4
- Norwogonin (5,7,8-THF)
- R7
- R13
- TDP6
|
---|
TrkC
| |
---|
|
---|
VEGF
| |
---|
Others
|
- Additional growth factors:
Adrenomedullin
- Colony-stimulating factors
(see
here
instead)
- Connective tissue growth factor (CTGF)
- Ephrins
(
A1
,
A2
,
A3
,
A4
,
A5
,
B1
,
B2
,
B3
)
- Erythropoietin
(see
here
instead)
- Glucose-6-phosphate isomerase (GPI; PGI, PHI, AMF)
- Glia maturation factor (GMF)
- Hepatoma-derived growth factor (HDGF)
- Interleukins
/
T-cell growth factors
(see
here
instead)
- Leukemia inhibitory factor (LIF)
- Macrophage-stimulating protein (MSP; HLP, HGFLP)
- Midkine (NEGF2)
- Migration-stimulating factor (MSF; PRG4)
- Oncomodulin
- Pituitary adenylate cyclase-activating peptide (PACAP)
- Pleiotrophin
- Renalase
- Thrombopoietin
(see
here
instead)
- Wnt signaling proteins
- Additional growth factor receptor modulators:
Cerebrolysin
(neurotrophin mixture)
|
---|
|
---|
Chemokine
| |
---|
CSF
| |
---|
Interferon
| IFNAR (α/β, I)
|
- Agonists:
Albinterferon
- Interferon alpha (interferon alfa, IFN-α)
- Interferon alfa
(
IFNA1
,
IFNA2
,
IFNA4
,
IFNA5
,
IFNA6
,
IFNA7
,
IFNA8
,
IFNA10
,
IFNA13
,
IFNA14
,
IFNA16
,
IFNA17
,
IFNA21
)
- Interferon alfa 2a
- Interferon alfa 2b
- Interferon alfa n1
- Interferon alfacon-1
- Interferon alpha-n3
- Interferon beta (IFN-β)
(
IFNB1
,
IFNB3
)
- Interferon beta 1a
- Interferon beta 1b
- Interferon kappa (IFN-ε/κ/τ/ζ, IFNK)
- Interferon omega (IFN-ω, IFNW1)
- Peginterferon alfa-2a
- Peginterferon alfa-2b
|
---|
IFNGR (γ, II)
| |
---|
IFNLR (λ, III)
|
- See IL-28R (IFNLR)
here
instead.
|
---|
|
---|
Interleukin
| |
---|
TGFβ
| |
---|
TNF
| |
---|
Others
| |
---|
|