Erythropoietin - Origin

Erythropoietin (EP [16]), also known as erythropoietin factor or EPO, is a humoral peptide hormone that is synthesized by cells of the kidney and is involved in regulating erythropoiesis, or red blood cell production (Silverthorn, 2009).

Figure 1: Molecular structure of erythropoietin. http://upload.wikimedia.org/wikipedia/commons/thumb/a/a1/Erythropoietin.png/250px-Erythropoietin.png

Hormonal regulation of erythropoiesis was first suggested in 1906 by Paul Carnot, a professor of medicine in Paris, and his co-worker Clotilde Deflandre (Jelkmann, 2007). In their experiment, the investigators subjected rabbits to a bloodletting wherein 30 mL of blood was obtained on the first day, a second blood sample was obtained the following day, after which the serum was injected into normal rabbits. The results showed that the concentration of erythrocytes increased up to 40% within two days (Jelkmann, 2007). The investigators concluded that the serum must have contained a hematopoietic factor, a chemical substance which stimulates the formation of blood cell components.

In 1948, researchers of red blood cell production, Eva Bonsdorff and Eeva Jalavisto from Helsinki, named this factor “erythropoietin” (Jelkmann, 2007).

 

 

Figure 2: Paul Carnot (left), and Allan Erslev(right). http://en.wikipedia.org/wiki/File:Paul_Carnot.jpg

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Allan Erslev, professor of medicine at Thomas Jefferson University, confirmed this finding and provided conclusive proof of the existence of EPO. He conducted an experiment in which large volumes of plasma (100-200 mL) was transfused from anemic rabbits (hematocrit below 20%) to normal rabbits (Jelkmann, 2007). The recipient rabbits responded with a significant increase in reticulocytosis, an increase in immature erythrocytes and after several days showed a higher hematocrit value of the blood (Jelkmann, 2007).

Erslev resolved that there must be a factor within the blood serum responsible for rapidly stimulating the production of red blood cells. He further predicted the therapeutic value of the erythropoietic factor in medicine, if it could be isolated and purified, against certain kidney disorders and infections (Jelkmann, 2007).

 

 

Figure 3: Scheme depicting biogenesis of erythropoietin.

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Figure 4: Hybridization studies on hypoxic monkey kidneys (C and D). Erythropoietin production by interstitial cells, showing EPO mRNA over peritubular interstitial cells (E), and in anemic mouse kidneys (F). http://ebm.rsmjournals.com/content/235/12/1398/F2.expansion.html

 

In further studies, EPO and EPO mRNA was extracted from the kidneys of hypoxic rodents. It was discovered that the hormone was primarily present in the cortex of the kidney (outer layer) and not in the medulla (Jelkmann, 2007). An in situ hybridization study indicated a subgroup of fibroblasts in the cells lining the peritubular capillary, as the site of EPO gene expression in the kidneys. Other organs, such as the liver, spleen, lung, bone marrow, and brain were shown to express EPO mRNA (Jelkmann, 2007). Erythropoietin from the brain is thought to act as a paracrine neuroprotective factor, as it is unable to enter the general circulation of the body due to the blood brain barrier (Jelkmann, 2007). 

Erythropoietin is a glycoprotein molecule consisting of 165 amino acids and contains over 40% carbohydrate, primarily sialic acid and other sugars (Hadley & Levine, 2007). The sialic acid residues in the molecule acts as a protectant, and is necessary for biological activity in vivo, as the absence of these residues (asialo form of EPO) causes the hormone to be cleared too rapidly by the liver, preventing it from exerting its hematopoietic effects (Hadley & Levine, 2007).

The purpose of EPO is to enhance the proliferation of erythrocyte precursor cells in the hematopoietic tissues (red marrow) of the bones or the fetal liver, into erythroblasts which are cells programmed to become erythrocytes (Hadley & Levine, 2007). The final result of this action is an increased number of erythrocytes in the blood, and therefore a higher hematocrit (Silverthorn, 2009).

 

EPO release is stimulated by hypoxic (low oxygen concentration) conditions in the tissues, and is inhibited during conditions which create tissue hyperoxia (high oxygen concentration). Any activity or agent which increases oxygen consumption and metabolic rate such as growth, high altitude exposure, hormones, and pharmaceutical agents, will increase the need for oxygen and subsequently stimulate EPO (Hadley & Levine, 2007). EPO action will increase red blood cells in the system, and therefore increase the oxygen transport to the tissues (Silverthorn, 2009).

Presently, erythropoietin is manufactured artificially using recombinant DNA technology because of its potential as a therapeutic agent and has already been used in treatment of anemia and certain cancers (Fisher, 2010). Preliminary studies have shown that mutations in certain regions of the peptide structure produce a neuroprotective protein without erythropoietic effects, which may be used to treat certain neurodegenerative diseases (Fisher, 2010).

References

- Silverthorn, D. U. (2009). Human Physiology, An integrated approach (5^th ed.). Benjamin Cummings, Pearson Education : San Francisco, CA

- Jelkmann, W. (2007). Erythropoietin after a century of research: younger than ever. European Journal of Haematology. Institute of Physiology, University of Luebeck: Luebeck, Germany

-  Hadley, M. E. & Levine, J. E. (2007). Endocrinology (6^th ed.). Prentice Hall, Pearson Education: Upper Saddle River, NJ

 

- Fisher, J. W. (2010) Landmark advances in the development of erythropoietin. Experimental Biology and Medicine. 235 (12): 1398-1411