Erythropoietin

Definitions & Key takeaways

Erythropoietin (EPO) is a hormone that regulates the production of red blood cells. EPO is produced by kidney cells, and can be deficient in individuals with chronic kidney diseases, resulting in reduced production of red blood cells, thus anemia.

EPO is made in response to low oxygen levels in the tissues. It signals the bone marrow to produce more red blood cells, which helps to increase oxygen delivery to tissues. EPO is also used as a doping agent in endurance sports because it can improve performance by increasing the amount of oxygen that is delivered to muscles. EPO doping has been reported to have negative health effects, including an increased risk of heart attack and stroke.

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Introduction0:00–0:53

With erythropoietin, ‘-poietin’ means ‘to make’ and ‘erythro-’ refers to red blood cells, so erythropoietin is a hormone that stimulates the production of erythrocytes or red blood cells in the bone marrow.
Erythropoietin, or EPO, is produced in the kidneys, and to a lesser extent in the liver, and travels through the blood to the bone marrow where it stimulates immature cells to transform into mature red blood cells.
Every cell in the body uses oxygen for cellular respiration. As we breathe, oxygen diffuses into the bloodstream where it binds hemoglobin within the red blood cells and gets carried off to various parts of the body.
Red blood cells live for about 120 days, so there is a constant need to produce new red blood cells. Now, in the bone marrow, there are proerythroblasts, which are primitive or immature red blood cells.

Functions0:53–1:46

The kidneys produce a constant level of erythropoietin, which gets released into the blood and makes its way to the bone marrow, where it binds to erythropoietin receptors on the immature red blood cells and causes them to erythrocytes, or mature into red blood cells, usually this production of erythropoietin is constant, so the production of mature red blood cells is constant.
If there’s ever decreased oxygen delivery to the tissues, then one thing the body can do is ramp up production of oxygen delivery vehicles, in other words red blood cells.
In this situation, the kidney cells ramp up production of erythropoietin, therefore ramping up production of mature red blood cells.
Interestingly, erythropoietin prevents immature red blood cells from killing themselves by apoptosis, meaning that without erythropoietin, developing red blood cells die via apoptosis.

Decreased oxygen delivery1:46–3:33

Fundamentally, decreased oxygen delivery to the tissues can be due to a decrease in blood flow or a decrease in blood oxygen content.
If there’s a decrease in blood flow, then increasing the number of red blood cells is not effective, however, if there’s decreased oxygen content like for example with,, then increasing the number of red blood cells will is effective and will help.
What’s neat is that the kidney can distinguish between these two situations. A decrease in blood flow means that the kidneys are less perfused, and it leads to less fluid getting filtered in the glomeruli.
Less fluid filtered means less solutes need to be reabsorbed and saved from being urinated out by the tubular cells, which requires energy from oxygen.
But in this case since there’s less solutes to reabsorb, the demand for oxygen by those tubular cells is low. So even though the oxygen supply decreases, the oxygen demand also decreases, meaning those cells still have enough oxygen, and so they don’t make erythropoietin.
On the other hand, with decreased oxygen content, there’s still a low oxygen supply, but an adequate blood flow, meaning more fluid gets filtered and more solutes get filtered and therefore need to be reabsorbed, which means the tubular cells need more energy and oxygen.
They now have a high demand for oxygen but again a low supply of oxygen, creating a state of oxygen starvation and stimulating the production of erythropoietin.

HIF1 in the kidneys3:33–5:24

Under normal conditions, the kidney cells produce a tiny promoter called hypoxia-inducible factor 1 or HIF1, which is made up of an alpha and beta subunit.
In the presence of oxygen, the enzyme HIF-prolyl hydroxylase, adds an -OH group also called hydroxylation, to the proline residues on the alpha subunit of HIF1.
As soon as these proline residues are hydroxylated, they get tagged with ubiquitin molecules, or ubiquitinated, which mark it for destruction within the organelle known as the proteasome, kind of the like the cellular woodchipper.
When there is an adequate level of oxygen within the kidney cells, the alpha subunits of HIF1 are constantly being destroyed in the proteasomes.
However, when the kidney cells are starved and so there’s an absence of O2, HIF1 doesn’t get hydroxylated and ubiquinated, sticks around as a result.
HIF1 goes into the nucleus of the cell and acts as a promoter to increase the synthesis of erythropoietin mRNA. In other words, as the demand for oxygen exceeds the supply of oxygen to the kidney cells, they start producing more erythropoietin.
All the cells in the kidney are capable of producing erythropoietin. Individuals with chronic kidney disease who have a loss of kidney mass, therefore have low erythropoietin levels and often develop anemia as a result.
The opposite situation occurs when exogenous erythropoietin is used, which leads to high erythropoietin and high red blood cell production.
Unfortunately this often used as an enhancement agent by athletes who want extra red blood cells to help them in sports like long-distance running and cycling.
All right, as a quick recap… erythropoietin is a hormone produced by the kidneys that helps in maturation of the red blood cells in the bone marrow.

Review5:24–5:42

When there is decreased oxygen delivery to the tissues, the kidneys increase erythropoietin production.