Erythropoietin Hormone and Its Functions in The Body

The idea of a “hormone” was not well-received by the scientific community, and it was a difficult concept to portray, as scientists had not been familiar with the idea of chemical messengers influencing the actions of cells in the body. Many scientists, such as Arnold Adolph Berthold, Thomas Addison, Joseph von Mering and Oskar Minkowski, George Murray, and George Oliver and Edward Albert Schäfer carried out experiments, studying the role of endocrine glands and their chemical messengers. However, their fellow scientists believed that the nervous system was responsible for the results of their experiments, not the chemical messengers (hormones) in the endocrine system. It was not until 1902, when two scientists, William Bayliss and Ernest Starling, demonstrated the mechanism of the hormone secretin and its ability to cause the secretion of bicarbonate in the form of pancreatic juice from the pancreas and into the duodenum during digestion. Following this discovery, endocrinology was acknowledged as an official branch of science, and these infamous chemical messengers that so many scientists attempted to corroborate, were finally defined as hormones.

A hormone is now understood as a chemical messenger, released in very small amounts from a cell, that exerts a biological action on a target cell. A well-recognized hormone today is erythropoietin (EPO). In 1906, Paul Carnot and Clotilde-Camille Deflandre proposed that there is a “humoral factor” that regulates erythropoiesis after noting an increase in red blood cells in rabbits after injecting them with anemic blood. Decades later, K. R. Reissman and Allan Erslev worked off the findings of Carnot and Deflandre and improved their experiment, further convincing the scientific community that there existed a chemical messenger that plays a crucial role in erythropoiesis. In 1977, Eugene Goldwasser and his team purified and isolated this chemical messenger. Over the years of scientists studying this factor, it has been named hemopoietine, erythropoietic-stimulating factor, etc. , until it was finally accepted as “erythropoietin” (American Society of Hematology).

EPO is a 165 amino acid glycoprotein with two disulfide bonds, which is produced primarily in the kidneys, and to a lesser extent in the liver. The exception to this is before birth and in individuals with loss in renal function. In both of these cases, the primary location of EPO synthesis is the liver. In the kidney, erythropoietin is synthesized by peritubular fibroblasts in the renal cortex. The secretion of EPO by the peritubular fibroblasts stimulates erythropoiesis (red blood cell production) in the bone marrow. The production of EPO is dependent on oxygen levels in tissues — lower levels of oxygen increase EPO production and secretion and high levels of oxygen decrease EPO production and secretion.

EPO has several targets and functions in the body. EPO has its effects on erythroid cells, non-erythroid cells, and non-erythroid tissue/organ systems alike. Specifically, EPO functions in bone marrow, which causes athletes to abuse its effects, in neurodevelopmemt, in cardiac tissue, in the intestines, in angiogenesis, and it functions to ameliorate obesity. As aforementioned, EPO stimulates erythropoiesis in the bone marrow. This occurs in response to low hematocrit, or ratio of red blood cells in the blood to the total amount of blood in the body. Low red blood cell levels in the blood means low oxygen levels in the blood, as red blood cells carry oxygen through the blood stream. Low oxygen levels in tissues can be the result of the body needing to replace red blood cells (due to a 120 day lifespan), shortened red blood cell lifespan, blood loss, low red blood cell production, or illnesses such as anemia (low red blood cell or hemoglobin levels in the blood). The kidneys are stimulated to release EPO in response to the hypoxia-inducible transcription factor complex, which regulates EPO release. This factor is highly expressed in low oxygen conditions and minimally expressed in high oxygen conditions. When the hypoxia-inducible transcription factor complex is expressed, EPO is released from the kidney and causes the differentiation of erythroid progenitors in the bone marrow, by binding to the EPO-receptor on these cells. This causes an increase in hematocrit, and therefore, an increase in oxygen-carrying capacity in the bloodstream. Due to the fact that EPO increases red blood cell levels in the blood, and therefore, increases oxygen-carrying capacity in the blood, EPO has been highly sought-after by athletes in an aim to engage in “blood doping”. Blood doping is when athletes take synthetic EPO in order to enhance their performance, due to the fact that they will have an increased oxygen capacity in their blood stream. However, many athletes do not realize that taking high doses of EPO causes oxidative stress, which results in the abundance of oxygen free radicals in the body, inundating antioxidants in the body with more free radicals than they can remove. Free radicals have a negative effect on the body’s cells, destroying many crucial cell organelles and components. Therefore, the doping of EPO has been banned in professional sports. Regardless, many athletes today, professional and nonprofessional, use EPO to enhance their athletic abilities.

EPO also plays a role in neurodevelopment. Specifically, when EPO is released from the kidney, it has a direct effect on neuroblastoma cells, causing them to differentiate, and on oligodendrocytes, increasing their number. This fact was manifested in a study done on infants with cerebral palsy. Specifically, synthetic EPO was shown to have healing effects on the infants, working as a neuroprotective factor. The same outcome resulted in another study with subjects that had acute stroke. EPO administration to these subjects showed to decrease the symptoms of stroke and ameliorate their condition overall. Additionally, a lack of EPO receptors in animal models, such as mice, resulted in a decrease in neural progenitor cells and apoptosis activity in the nervous system, indicating EPO is necessary for proper neural function and maintenance. Furthermore, in studies performed in vivo, EPO was shown to, again, work as a neuroprotective factor, protecting against brain injury.

Moreover, EPO aids in cardiac function. In an in vivo study conducted on rats with myocardial infarction, administration of EPO greatly reduced apoptosis of cardiomyocytes, strengthening cardiac function and increasing the cardiac lifespan. EPO increases the likelihood of endothelial cell survival against a possible ischemic injury on the vessels in the heart, by also preventing apoptosis (Bunn 2013). Likewise, in humans that have myocardial infarction, EPO is shown to have healing properties, as it stimulates the formation of new capillaries in the heart. In fact, recombinant human EPO (rhEPO) has been used to decrease the size of an infarction, and in the process, aid in the restructuring of the left ventricle. Additionally, EPO has been used in many studies, concerning patients with congestive heart failure. In these patients, EPO was shown to improve cardiovascular function and efficiency. Researchers indicate this finding is so because anemia is found to worsen congestive heart failure, and EPO works on bone marrow to increase red blood cells in the blood, therefore, eliminating the anemic state.

Another function of EPO is eliminating inflammation in the intestines and aiding in intestinal regeneration. EPO eliminates inflammation in the intestines in various ways, including inhibiting the immune response in intestinal tissue. This is so because the immune response is accompanied by inflammation due to macrophage activation and release. This mechanism was supported in a study using mice with colitis, or inflammation of the colon (large intestine). The mice were given EPO, and the EPO was found to inhibit macrophage release and pro-inflammatory gene expression. Also, EPO was found to down-regulate interleukins in the colon, which also cause an inflammatory immune response, further supporting the idea that EPO suppresses immune function in order to decrease inflammation. These factors, together, severely decreased colitis in the mice. In terms of intestinal regeneration, a study analyzing EPO receptor expression in the human body confirmed that EPO receptors are, in a large quantity, expressed in the large intestine. Thus, EPO administered to humans has been shown to stimulate the production and growth of epithelial cells in the large intestine, regenerating the colon.

EPO has also been observed to support and enhance angiogenesis, or the generation of blood vessels, and to maintain blood vessel function. In studies conducted in vitro, administration of EPO up-regulated proteins on the cell surface of endothelial cells, causing an increase in the strength of tight junctions. This mechanism is especially important in the blood-brain barrier where tight junctions are an integral part of allowing the blood-brain barrier to work optimally in its very selective permeability. Also, EPO has its effects on endothelial progenitor cells. EPO increases the differentiation of these cells, which in turn, stimulates angiogenesis and endothelial restoration and recovery. Regarding EPO functioning to maintain blood vessel function, a study using a culture of rat endothelial cells revealed that EPO increases the expression of nitric oxide synthase. Nitric oxide synthase is responsible for producing nitric oxide, which controls vascular contraction to allow for efficient movement of blood, ultimately, sustaining proper blood vessel function.

Further, another study conducted in vivo in rats, demonstrated that administered EPO decreased the likelihood of vascular impairment. Furthermore, EPO can also serve as a “therapeutic agent” towards obesity. A study using mice subjects found that obese mice that ate high-fat diets and then had EPO administered to them, showed a notable decrease in body weight. This was due to EPO increasing the metabolism in these mice, through causing an increase in oxygen-consumption in the electron transport chain. EPO also reduced the accumulation of white adipose tissue and increased the differentiation of brown adipose tissue cells, which both cause a decrease in overall body weight. In another study using animal modes, EPO was found to affect the inflammatory response of white adipose tissue. Subjects treated with EPO saw inhibitory effects on cytokine expression in white adipocytes (cytokines cause inflammation in the immune response), delineating the idea that EPO decreases inflammation caused by obesity.

Ultimately, it is clear that EPO has various functions, which have their effects on many different cells, tissues, and organs. EPO is well known for its effect on bone marrow to cause the differentiation of erythrocytic progenitors, in order to produce red blood cells. However, scientists and the masses, alike, are still learning about the many non-erythroid effects of EPO, and much is still to be studied and discovered, as all of the functions of EPO are not well understood. Still, there is a lot of information regarding the misuse and abuse of EPO, the ability of EPO to affect neurodevelopmemt, cardiac tissue, the intestines, angiogenesis, and the hormone’s ability to ameliorate obesity.