Erythropoietin and hypoxia: how the kidney raises red cell production
Erythropoietin (EPO), a hormone made mainly in the kidney in response to hypoxia (low oxygen supply to tissues), keeps cells committed to becoming red cells alive in the marrow.
Remember
When oxygen delivery to the tissues falls, the kidney releases erythropoietin, which stops immature red cell precursors in the marrow from dying, so more red cells are made until oxygen delivery is restored.
Memory aid
The kidney is the body's oxygen smoke alarm, and EPO is the alarm call that tells the marrow to make more red cells.
The kidney senses low oxygen like a smoke alarm, and EPO is the call that sends the marrow to work.
Red blood cells (erythrocytes) have a lifespan of 120 days, so the supply needs frequent replenishing. The amount of red cell production can vary. In hypoxia (reduced oxygen supply to the tissues), more erythrocytes can be formed.
The kidney detects low oxygen in the tissues. Interstitial peritubular cells (cells in the supporting tissue between the kidney tubules) detect the low oxygen supply and raise production of erythropoietin (EPO). The liver also makes EPO, but to a smaller extent than the kidney.
EPO travels in the blood to the bone marrow and acts on erythroid progenitor cells, immature cells already committed to becoming red cells. These cells are programmed to die unless they receive a survival signal, and EPO supplies it by preventing apoptosis (programmed cell death). With more progenitors surviving, more of them pass through the reticulocyte stage (young red cells that have just lost their nucleus) and enter the blood, where they mature into erythrocytes within about two days.
A higher red cell count and more haemoglobin let the blood carry more oxygen, relieving the hypoxia. The EPO signal then falls, because the correction removes the stimulus. This is a negative feedback loop, a system that switches itself off once the problem is corrected. The same loop explains why people living at altitude have a higher haematocrit (the proportion of blood that is red cells).
Red cell production also needs raw materials. Iron is needed to make haemoglobin, so severe iron deficiency can limit the response even when the EPO signal is strong.
Key facts
- Hormone
- EPO is made mainly in the kidney, and the liver makes some to a smaller extent.
- Sensor
- interstitial peritubular cells in the kidney detect hypoxia.
- Target
- erythroid progenitor cells in the bone marrow.
- Action
- EPO prevents apoptosis, so more progenitors survive and mature into red cells.
- Outcome
- reticulocytes mature into erythrocytes over about two days, and the rise in red cells builds over days.
- Feedback
- more red cells raise oxygen delivery, so EPO release falls.
- Other blood cell lines
- thrombopoietin stimulates platelet production, and granulocyte colony-stimulating factor (G-CSF) stimulates production of granulocytes (neutrophils, basophils and eosinophils), mainly neutrophils.
Exam traps
- The lungs do not release the erythropoietin that raises red cell production; it is made mainly in the kidney, and the liver makes some to a smaller extent.
- Contraction of the spleen can push stored red cells into the blood, but that is release of cells already made rather than new production, and in humans the red cell store of the spleen plays only a small part.
- Thrombopoietin is the hormone for platelet production by megakaryocytes (the large marrow cells that break up into platelets), so it does not drive red cell production.
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