Erythropoietin - Functions, Production, Regulation and Mechanism of Action

Introduction

Erythropoietin (EPO) is a crucial hormone or growth factor secreted by the kidneys and the liver (ten percent) that is responsible for the synthesis and maintenance of red blood cells in the bone marrow. EPO (erythropoietin) synthesis is increased in case of cellular hypoxia, and an imbalance in the levels of EPO occurs due to multiple systemic problems like anemia, cancer, chronic, and long-standing kidney diseases.

What Is Erythropoietin (EPO)?

Erythropoietin (EPO) is a crucial hormone produced primarily by the kidneys, and it regulates the production of red blood cells from the bone marrow. Erythropoietin is classified as a glycoprotein cytokine. This hormone is secreted from the kidneys in response to reduced oxygen levels in the tissue (known as cellular hypoxia). A small amount of erythropoietin is constantly secreted to compensate for physiologic red blood cell turnover; the average lifespan of a red blood cell is one hundred and twenty days, and it is renewed every day. Erythropoietin is produced by interstitial cells of the kidneys; these cells are capable of responding to cellular hypoxia. When the cells reach a sufficient level of oxygen, the production of erythropoietin is reduced. This is an adaptive mechanism of the body.

What Are the Other Names of Erythropoietin?

• EPO.

• Hematopoietin.

• Hemopoietin.

What Are the Functions of Erythropoietin?

• The primary function of EPO is the production and maintenance of red blood cells produced by the bone marrow in response to cellular hypoxia.

• Once these red blood cells are produced, EPO also helps in protecting these cells.

• Stimulation of differentiation and proliferation of these red blood cells via binding to the erythropoietic receptors.

• Initiate the production of hemoglobin (proteins present in the red blood cells that carry oxygen to tissues).

• EPO is also known to stimulate vasoconstriction-induced hypertension, the formation of new blood vessels from older vessels, and the promotion of cell survival by activation of EPO receptors.

How Is Erythropoietin Produced and Regulated?

EPO is mainly produced by the interstitial capillary bed of the renal cortex. About ten percent of EPO is produced in the perisinusoidal cells of the liver. However, the production of EPO by the liver is limited to fetal and perinatal time (the short period immediately before and after childbirth). The gene carrying information about EPO is located on human chromosome 7. Some additional amount of EPO is produced in the multifunctional mural cells (pericytes) of the brain. The regulation of EPO synthesis is primarily based on blood oxygen levels and iron availability. In the absence of hypoxia, the EPO levels are normal, but during hypoxia stress, this level increases about 1000 times. In normal conditions, the promoter gene of EPO is inhibited, whereas, during hypoxia, it is increased to promote the production of EPO.

What Is the Mechanism of Action of Erythropoietin?

EPO binds to the receptors present on the cell surface of colony-forming unit-erythrocytes (CFU-E), proerythroblast (precursor cells of erythrocytes), and basophilic erythroblasts in the bone marrow. EPO binding to its receptor leads to the prevention of physiologic apoptosis (programmed cell death).

What Are the Normal Erythropoietin Levels?

The normal EPO level is around 10 mU/ml (milliunits per milliliter), and the normal range of EPO is considered to be between 4 to 24 mU/mL. For males, this range is between 5.8 to 9.9 international units per liter, and for females, it is around 6 to 10.6 international units per liter. This normal level of EPO increases up to 1000 mU/mL during hypoxia.

What Happens if There Is Excess of Erythropoietin?

Increased levels of EPO occur when there is prolonged and chronic exposure to low oxygen levels in the tissues. This increased amount of EPO leads to a condition known as polycythemia (high red blood cell count). Excess EPO usually occurs due to the presence of a tumor, and the symptoms of excess EPO include:

• Weakness and fatigue.

• Dizziness.

• Headache.

• Itching.

• Joint pain.

However, these symptoms are non-specific and may be associated with multiple other diseases. In rare cases, excess EPO can be associated with serious health risks like

• Increased viscosity of the blood.

• Reduced effective blood supply.

• Reduced blood oxygenation.

• Increased blood pressure in the lungs.

• Blood clots.

• Strokes.

What Happens if There Is a Lack of Erythropoietin?

Lack of EPO leads to reduced red blood cells, which, in turn, leads to anemia. In addition, anemia is the most prevalent complication of reduced EPO. Reduced EPO occurs due to chronic kidney diseases and bone marrow disease. It may also occur due to the presence of some type of cancer in the body. The symptoms of EPO deficiency include:

• Fatigue and weakness.

• Light-headedness.

• Breathlessness.

• Headaches.

• Pale skin.

• Heart palpitations.

How Is Erythropoietin Tested?

EPO levels can be easily tested through blood examination. Blood tests are done like any other regular blood test, and patients generally do not have to prepare for them. The test is done in the following ways:

• Blood samples are collected from the veins.

• The sample is usually collected in the morning.

• The patient should fast for eight to nine hours (overnight) before the test.

• Sometimes, the doctor may advise a complete blood count to be done before EPO testing.

• The collected sample is sent to the laboratory to check for the level of EPO present in the blood.

• The patient should inform their healthcare provider if they are taking drugs or supplements before going for the test.

What Is Recombinant Erythropoietin?

Recombinant human erythropoietin is an erythropoiesis-stimulating agent that is used for various diseases that cause a reduction in red blood cell count. Recombinant erythropoietin is used for the treatment of chronic anemia, kidney diseases, cancer, and human immunodeficiency virus infection (HIV). It is marketed in three forms:

• Epoetin ɑ.

• Epoetin β.

• Epoetin δ.

• Epoetin Ω.

These drugs can be given in the form of injections.

What Is Erythropoietin Doping?

The use of recombinant erythropoietin by athletes to improve their performance is very common malpractice, and it is known as erythropoietin doping. EPO doping exponentially increases the number of red blood cells, which eventually increases the oxygen concentration in the muscles. This increased oxygen supply to the muscles helps athletes in performing abilities and endurance. However, this doping is illegal and banned in all professional sports in all countries. The International Olympics committee banned EPO doping in the year 1990. Two philosophies are developed to detect recombinant human EPO in the blood; the first is based on indirect blood markers, and the second is based on the direct detection of recombinant human EPO in the urine.

Conclusion

The use of recombinant EPO has been constantly misused by athletes and sports professionals to enhance and improve their performance. However, EPO doping has been strictly prohibited all over the world in every professional sport. Athletes have to undergo various screenings before the competition to get their serum EPO levels checked.