Erythropoietin (Hormone)

Erythropoietin (Epo) is a hormone produced by the kidneys in response to hypoxia and is also a prescription drug used in treatment of severe anemia. This page discusses the hormone in the context of normal and abnormal physiology. For more on the drug, see Erythropoietin (Drug).

Contents 1 Description 2 Role of Erythropoietin in the Body 3 How It Works 4 Diseases of Erythropoietin 4.1 Inadequate erythropoietin 4.2 Too much erythropoietin 5 History 6 References

Description

Epo is a glycoprotein with a molecular mass of 30.4 kD. It is made up of many amino acids and carbohydrates. ^[1] The carbohydrates allow for many possible shapes and contribute to stability of erythropoietin in living humans.

Epo is produced in the kidneys in adults, and in liver cells in the fetus. In adults, a small amount of Epo is produced by the liver. The rate of Epo synthesis and secretion depends on local oxygen concentrations. Lack of oxygen is the main stimulus for Epo production. The serum concentration of Epo in adults is normally 4-27 mU/mL. In adults with anemias not resulting from kidney disease, the serum concentration of Epo tends to increase with the severity of the anemia.

Role of Erythropoietin in the Body

The role of Epo is to maintain an appropriate level of red blood cell production by the bone marrow. In the absence of Epo stimulation, RBC production stops, and cells in the marrow that give rise to RBCs undergo a regulated process of self-destruction known as apoptosis.

How It Works

Like all hormones, Epo is made and released from one part of the body in a regulated fashion, travels to another part of the body, and initiates a coordinated response a short time later. Epo's activities depend on successful interaction with its receptor, which is prominent on the surface of developing RBCs in the bone marrow. Epo signaling acts to prevent or retard apoptosis, i.e., it acts as a survival factor for developing cells. The increase in RBC mass brought about by Epo stimulation of the bone marrow completes a self-regulating feedback loop. Other things being equal, the increased RBC mass usually increase oxygen levels experienced by the kidney. This results in decreased Epo production, whose levels do not need to be so high when there is sufficient RBC concentration to maintain adequate oxygen levels in the blood.

Diseases of Erythropoietin

Inadequate erythropoietin

Inadequate Epo production is uniformly associated with abnormally low RBC production rates and a hypoproliferative anemia. Symptoms of anemia include pale skin, exercise intolerance, and lightheadedness. Treatment decisions depend on the urgency of the situation and on the underlying disease process, but may include blood transfusion or synthetic Epo administration.

• Severe aplastic anemia occurs rarely. In some people treated with Epo, neutralizing antibodies to Epo may develop. These bind to and prevent Epo from acting normally—this life-threatening condition cannot be treated with synthetic Epo and often results in long-term dependence on blood transfusions.
• Chronic kidney disease is classically associated with anemia, low Epo levels, and an intact bone marrow. It responds well to periodic Epo injections.
• Chemotherapy-induced anemia is a concern in treating cancer patients receiving chemotherapy. Epo is approved for use in this context.
• Space flight anemia results from a transition to the low (or no) gravity of outer space. Under the influence of normal gravity, blood tends to sink from the head to the legs. This tendency vanishes when astronauts are in orbit, and the "extra" blood previously stored in the veins of the legs enters the central circulation, resulting in extra oxygen delivery to the kidneys. The kidneys respond by shutting down Epo production, which lowers RBC production. A second feature of space flight anemia is destruction of young RBCs, a process called neocytolysis. ^[2]

Too much erythropoietin

Polycythemia (high concentrations of RBCs in peripheral blood) results from high levels of Epo. This may provide an advantage in some circumstances, such as living at high altitudes in the Andes Mountains. However, increasing the RBC mass also tends to make the blood thicker, which makes it flow less easily through smaller blood vessels. This change in blood rheology can increase the tendency for blood to clot, causing problems such as strokes and heart attacks. Other examples of high Epo activity can be found in families with a genetic tendency to have high RBC volume (familial erythrocytosis). Mutations in Epo or the related proteins that accelerate RBC production have been identified.^[3]

History

Carnot and DeFlandre ^[4] made initial observations in rabbits that suggested the existence of a factor in peripheral blood that could stimulate production of reticulocytes (the precursor cells for RBCs). Their experiment involved bleeding a rabbit to induce accelerated RBC production, then transfering some of this animal's blood to a recipient animal. The key observation of increased reticulocytes in the recipient animal prompted the search for a substance, which they named hemopoietin, that regulated the rate of RBC production.

A major breakthrough came In 1977 when small amounts of erythropoietin were purified from the urine of patients with aplastic anemia.^[5] Amino acid sequence data from this protein were used in subsequent efforts to clone the gene for erythropoietin in 1983.^[6]

References

1. ↑ Browne JK, Cohen AM, Egrie JC, et al. Erythropoietin: gene cloning, protein structure, and biological properties. Cold Spring Harb Symp Quant Biol. 51:693-702, 1986. Abstract
2. ↑ De Santo NG, Cirillo M, Kirsch KA, et al. Anemia and erythropoietin in space flights. Semin Nephrol. 2005 Nov;25(6):379-87. Abstract
3. ↑ Percy MJ, Furlow PW, Lucas GS, et al. A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N Engl J Med. 2008 Jan 10;358(2):162-8. Abstract
4. ↑ Carnot P, DeFlandre C. Sur l’activit´e h´ematopoi´etique des diff´erents organes au cours de la r´eg´en´eration du sang. C. R. Acad. Sci. Paris 143:432–435, 1906
5. ↑ Miyake T, Kung CK, Goldwasser E. Purification of human erythropoietin. J Biol Chem 252:5558-5564, 1977 Abstract
6. ↑ Lin FK, Suggs S, Lin CH, et al., Cloning and expression of the human erythropoietin gene. PNAS 82: 7580-7584, 1985. Abstract PDF