HISTORY OF ERYTHROPOIETIN

Hi friends, 

Today, 11 March 2021 is celebrated as ‘World Kidney Day’.

And the motto for this year is ‘Living well with Kidney disease’.

I thought of writing a post related to Kidney and hematology and that’s why todays’ topic is about erythropoietin. 

What is erythropoietin?

¨     Erythropoietin abbreviated as Epo, is a glycoprotein hormone that controls erythropoiesis

¨     It has a molecular weight of 30.4 kDa

¨     Epo circulates in plasma with a plasma half-life of ∼7–8 hours

¨     It is produced by interstitial fibroblasts in the kidney

¨     It is also produced in perisinusoidal cells in the liver

¨     Liver production predominates in the fetal and perinatal period, while renal production during adulthood

¨     Other than erythropoiesis, erythropoietin has an important role in the brain's response to neuronal injury (Siren et al., 2001)

¨     It is also involved in the wound healing process (Haron et al., 2003)

Do you know what, it was interesting to know how the research on erythropoietin had started years back. 

à      In 1890, Viault had observed that after travelling for two weeks in Peru from sea level (Lima) to Morococha ,mountain area which is at a height of 4200- metres, his red blood cell (RBC) counts increased from 5.0 million to 7.1 million/mm³. RBC counts of five other sojourners, who travelled with him also increased, from 7.1 to 8.0 million. Though these are simple observations, they provided the first convincing demonstration of the robust increase in erythropoiesis in man soon after exposure to high altitude hypoxia. 

The mechanism underlying this phenomenon was a topic of heated debate in the next coming years. 

à      In 1893, Friedrich Miescher, who was already well known for his discovery of DNA, proposed that decrease in oxygen tension within the bone marrow provided direct stimulus to erythroid cells. But this theory was disproven, over half a century later by Berk et al (1948) and Stohlma et al (1954).

à      In 1906, Carnot and Deflandre proposed an alternate mechanism for hypoxic induction of erythropoiesis. They did study on normal rabbits, by infusing serum from anemic animals, and observed an increase in red blood cell counts and concluded that erythropoiesis is regulated by a humoral “factor” in the plasma. But this experiment could not be reproduced.

à      In 1943 by Krumdieck and in 1953 by Ersley, modified the experimental design of Carnot and Deflandre and convincingly showed the induction of new red cell production within 3–6 days following injection of anemic serum.

Are you curious to know what they modified? Yes, they modified by adding accurate measurements of reticulocytes.

à      Next, the concept involving an indirect humoral mechanism was strongly supported by experiments by Reissmann and Ruhenstroth Bauer in 1950. 

à      So, all these studies led to the concept of a circulating erythroid-stimulating hormone, “erythropoietin”.

à      Organ ablation studies in rats by Jacobson et al in 1957, then later by Nathan et al in 1964 in man, firmly established that the kidney was the major site of Epo production. 

à      By 1977, Goldwasser and his team were able to prepare 8 mg of highly purified human Epo.

à      In 1985, molecular cloning of Epo gene was done by Jacobs et al and Lin et al, which later led to many advances and the preparation and use of erythropoiesis stimulating agents with therapeutic implications. 

References:

 H.Franklin Bunn. Erythropoietin. Cold Spring Harb Perspect Med. 2013 March;3(3). 

                                                                                                                                                                          Written by Dr.Priyavadhana