Erythropoietin is produced primarily by specialized cells in the kidneys, with the liver serving as a secondary source and several other tissues contributing smaller amounts. About 90% of the hormone comes from the kidneys in healthy adults, specifically from a population of cells nestled in the spaces between the kidney’s tubules. But this tidy picture gets more interesting when you consider that the body’s EPO geography shifts dramatically during fetal development, that the brain makes its own local supply, and that kidney disease disrupts the system in ways that affect millions of people worldwide.
The Specific Cells That Make EPO in the Kidney
EPO does not come from the kidney’s filtering units or from the cells lining its tubules. Instead, it is produced by fibroblast-like interstitial cells that sit in the spaces around the peritubular capillaries, the tiny blood vessels that wrap around the kidney’s tubules in the cortex and outer medulla. Research in mice first pinpointed these peritubular cells as the source, showing that glomerular and tubular cells were not involved and that the positive cells were located in the cortex and, to a lesser extent, the outer medulla.1PubMed Central. Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidney Later work in genetically modified anemia mice confirmed this, using fluorescent tagging to show that EPO-expressing cells were stellate-shaped fibroblasts nestled around proximal tubules in the deep cortical labyrinth.2PLOS ONE. Isolation and Characterization of Renal Erythropoietin-Producing Cells from Genetically Produced Anemia Mice
The same cell type has been confirmed across species. In monkeys, EPO messenger RNA was found exclusively in interstitial cells in the peritubular capillary bed, matching the pattern seen in mice, rats, and sheep. Because the same cell type produces EPO in a higher primate, researchers consider it strong evidence that human EPO production follows the same pattern.3PubMed. Erythropoietin production by interstitial cells of hypoxic monkey kidneys The location makes physiological sense: these cells are sandwiched between the blood supply and the oxygen-consuming tubular cells, which positions them perfectly to detect changes in oxygen delivery.
How Oxygen Levels Control EPO Production
The kidney acts as a remarkably sensitive oxygen sensor. When blood oxygen drops, whether from blood loss, anemia, lung disease, or high altitude, a transcription factor called hypoxia-inducible factor (HIF) accumulates inside the EPO-producing cells. Under normal oxygen conditions, enzymes called prolyl hydroxylases tag HIF for rapid destruction. When oxygen falls, those enzymes slow down, HIF stabilizes, and it switches on the EPO gene.4American Journal of Physiology-Renal Physiology. Hypoxic regulation of erythropoietin and iron metabolism The result is a surge of EPO into the bloodstream, which travels to the bone marrow and drives the production of new red blood cells.
This system does not operate in open-loop fashion. The circulating red blood cell mass itself feeds back on the sensitivity of the EPO-producing cells. Experiments in rats showed that animals with higher hematocrit levels had a blunted EPO response to the same degree of hypoxia, suggesting the red cell mass acts as a brake on the system’s sensitivity.5Blood. Feedback Regulation by Red Cell Mass of the Sensitivity of the Erythropoietin-producing Organ to Hypoxia The whole apparatus has evolved to keep red blood cell levels within a narrow physiological range while still being able to respond rapidly to emergencies like hemorrhage or sudden hypoxia.6PubMed Central. Erythropoietin regulation of red blood cell production: from bench to bedside and back
The Fetal Liver and the Switch at Birth
Before birth, the liver is the main EPO factory. The fetus relies heavily on hepatic EPO production to support the rapid expansion of red blood cells needed during development. Sometime around birth, production shifts from the liver to the kidneys, a transition long attributed to the dramatic increase in oxygen exposure when a baby starts breathing air. But the picture turns out to be more nuanced than that.
Research tracking EPO profiles in newborns of different gestational ages found that the shift from hepatic-like to renal-like EPO production was tied to developmental age, not to how long the infant had been breathing atmospheric oxygen. Preterm infants retained hepatic-like EPO profiles for weeks after birth despite continuous oxygen exposure, suggesting that intrinsic liver maturation, rather than oxygenation, governs when the liver stops being the dominant EPO source.7eBioMedicine. Biological maturation drives the hepatic-to-renal switch in erythropoietin production at birth This has practical implications for understanding anemia in premature infants, whose EPO regulation may not follow the timeline clinicians assumed.
EPO Production in the Brain
The kidneys handle the body’s systemic EPO needs, but the brain maintains its own local supply. Astrocytes, the star-shaped support cells in the central nervous system, produce EPO in response to low oxygen.8PubMed Central. Role of erythropoietin in the brain This matters because very little circulating EPO crosses the blood-brain barrier, even when it is administered intravenously at high doses. The brain essentially needs to make its own.
The EPO produced by astrocytes appears to serve a protective role for neurons. Laboratory experiments using astrocyte cell lines showed that the EPO they released into surrounding fluid protected cultured neurons from glutamate-induced cell death, a form of toxic damage that occurs during strokes and other brain injuries.9PubMed Central. In vitro neuroprotective action of recombinant rat erythropoietin produced by astrocyte cell lines Further experiments found that when astrocytes were subjected to oxygen-glucose deprivation followed by cooling (mimicking therapeutic hypothermia after brain injury), the EPO they released reduced neuronal death. Blocking EPO signaling with neutralizing antibodies eliminated this protective effect.10PubMed Central. Prolonged astrocyte-derived erythropoietin expression attenuates neuronal damage under hypothermic conditions So brain-derived EPO appears to be part of the nervous system’s own damage-control toolkit, separate from its well-known role in making red blood cells.
The Placenta and Other Peripheral Sources
During pregnancy, the placenta becomes another EPO production site. Researchers identified EPO protein and messenger RNA in several types of placental cells across all three trimesters, including in trophoblast cells that form the interface between mother and fetus. Placental cells grown in culture produced EPO that was released into surrounding fluid, and production increased under low-oxygen conditions.11PubMed. Expression of erythropoietin by the human placenta The exact role of placental EPO is still being worked out, but it may help regulate local blood vessel growth or support fetal red blood cell production.
EPO receptors are also found in the cardiovascular system, including on endothelial cells and heart muscle cells. Animal studies have shown that EPO signaling in the heart limits damage during ischemia, and that EPO may promote the growth of new blood vessels in oxygen-starved tissue.12PubMed. Protective effects of erythropoietin in cardiac ischemia: from bench to bedside More broadly, EPO receptor expression across non-blood-forming tissues has been linked to wound healing, blood vessel formation, and the body’s built-in response to injury in both the brain and heart.13PubMed. The non-haematopoietic biological effects of erythropoietin
What Happens When the Kidneys Fail
Chronic kidney disease is where the clinical consequences of EPO’s renal origin become starkly apparent. As kidney function declines, the specialized fibroblasts that produce EPO undergo a transformation: they turn into myofibroblasts, scar-forming cells that contribute to kidney fibrosis but lose their ability to make EPO.14Journal of the Formosan Medical Association. Physiology and pathophysiology of renal erythropoietin-producing cells The result is a progressive drop in EPO output. Since EPO drives the final stages of red blood cell maturation in bone marrow, the deficit leads to a characteristic anemia that is one of the most common complications of advanced kidney disease.15PubMed. Erythropoiesis and chronic kidney disease-related anemia: From physiology to new therapeutic advancements
Detailed lineage-tracing work in mice has shown that the EPO-producing fibroblasts in healthy kidneys largely originate from cells that migrated into the embryonic kidney from outside it. In diseased kidneys, these same fibroblasts transdifferentiate into myofibroblasts and become the dominant contributors to fibrosis, simultaneously losing EPO production.16PubMed Central. Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice This creates a vicious cycle: the very process that scars the kidney also eliminates the cells responsible for preventing anemia. The liver’s residual EPO production cannot compensate adequately, which is why kidney disease anemia requires medical intervention.
Drugs That Coax the Body Into Making More EPO
For decades, the standard treatment for kidney disease anemia was to inject synthetic EPO (or one of its longer-acting relatives) directly. A newer class of oral drugs takes a different approach: rather than replacing the missing hormone, these drugs trick the body’s own oxygen-sensing machinery into producing more. Called HIF prolyl hydroxylase inhibitors (HIF-PHIs), they block the enzymes that normally destroy HIF under normal oxygen conditions. With HIF stabilized, the EPO gene is activated even in damaged kidneys, and even in patients with end-stage kidney disease.17American Journal of Kidney Diseases. Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors: A Potential New Treatment for Anemia in Patients With CKD
Beyond boosting EPO, these drugs also lower hepcidin, a liver hormone that restricts iron availability. By improving iron metabolism at the same time as stimulating EPO production, HIF-PHIs may reduce the need for intravenous iron supplementation that many kidney disease patients currently require alongside their EPO injections.18PubMed Central. Hypoxia-inducible factor-prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease Several of these drugs are now approved in various countries, though long-term safety data is still accumulating.
Altitude and the EPO Surge
High altitude provides a natural window into how quickly the kidneys ramp up EPO production. When lowlanders ascend to altitude, circulating EPO levels begin rising within hours. In one study, EPO was significantly elevated after just six hours at altitudes as low as about 1,800 meters and continued climbing after 24 hours at higher elevations.19PubMed. Determinants of erythropoietin release in response to short-term hypobaric hypoxia Individual variation is enormous, though: at 2,800 meters, the 24-hour EPO response ranged from a slight decrease in some people to a fourfold increase in others.
At more extreme altitudes, the response is more dramatic. In lowlanders brought to about 4,300 meters, EPO concentration rose roughly sixfold by 24 hours and peaked at over thirteenfold above baseline by 48 hours before gradually declining, though levels remained elevated past 72 hours.20PubMed Central. High-Altitude Hypoxia Decreases Plasma Erythropoietin Soluble Receptor Concentration in Lowlanders The subsequent decline even while the person remains at altitude reflects the feedback loop described earlier: as new red blood cells enter circulation and oxygen delivery improves, the stimulus for EPO production diminishes. This is why athletes who train at altitude see diminishing EPO levels after the first few days, even though their red blood cell mass continues to climb for weeks.
When Tumors Produce EPO
Occasionally, tumors start producing EPO on their own, leading to an abnormal increase in red blood cells called secondary erythrocytosis. The most commonly implicated tumors are kidney cancers, which makes sense given the kidney’s native EPO-producing role. But tumors in the liver, uterus, ovary, adrenal glands, and central nervous system have all been documented as ectopic EPO sources.21Blood. Erythropoietin Synthesis by Tumor Cells in a Case of Meningioma Associated With Erythrocytosis
Among brain tumors, cerebellar hemangioblastomas are the most frequent culprits. These are rare, slow-growing tumors of the blood vessels in the cerebellum. Researchers confirmed one such tumor as a genuine EPO production site by finding EPO messenger RNA directly within the tumor tissue and elevated EPO levels in the tumor’s cyst fluid.22Blood. Secondary Erythrocytosis Due To a Cerebellar Hemangioblastoma: Demonstration of Erythropoietin mRNA in the Tumor In these cases, the erythrocytosis typically resolves after the tumor is removed, confirming it as the source. For clinicians, unexplained erythrocytosis can be an early clue pointing toward one of these otherwise hard-to-detect tumors.
How EPO Acts on the Bone Marrow
Once released into the bloodstream, EPO’s primary target is the bone marrow, where red blood cell precursors carry EPO receptors on their surface. EPO binds to these receptors and triggers signaling that does two things simultaneously: it promotes survival of the precursor cells (preventing them from dying before they mature) and it drives the final stages of red blood cell development. The system is capable of scaling production from a steady baseline of billions of new red cells per day to much higher output during hemorrhage, hemolysis, or altitude acclimatization.23PubMed Central. Erythropoietin (EPO) as a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial Transdifferentiation of Multipotent Mesenchymal Stem Cells (MSCs): Implications in Regenerative Medicine
Without adequate EPO, red blood cell precursors undergo programmed cell death before they can mature. This is precisely the problem in kidney disease anemia: it is not that the bone marrow itself is damaged, but that the marrow never receives the signal to finish the job. Provide the EPO, whether by injection or by coaxing the kidney remnant to produce more with HIF-PHI drugs, and the marrow responds.
Making EPO in the Lab
The story of synthetic EPO begins with the laborious purification of the natural hormone from the urine of severely anemic patients, who produce it in large quantities. Early purification efforts in the 1970s and 1980s yielded preparations with potencies around 70,000 to 80,000 units per milligram of protein, enough to characterize the molecule and eventually clone the gene.24Blood. Purification of Human Erythropoietin to Homogeneity by a Rapid Five-Step Procedure25Journal of Biological Chemistry. Purification of human erythropoietin Once the gene was cloned, recombinant EPO could be produced in cell culture on an industrial scale.
Most commercial EPO is made in Chinese hamster ovary (CHO) cells, which add sugar chains to the protein in patterns similar, but not identical, to those on the natural human version. The resulting molecule weighs roughly 33 to 37 kilodaltons and carries heavy glycosylation that is critical for its activity and survival time in the bloodstream.26PubMed. The effect of dissolved oxygen on the production and the glycosylation profile of recombinant human erythropoietin produced from CHO cells When a version of EPO was produced in a human cell line instead of CHO cells, it showed meaningful differences in its sugar-chain patterns, including different types and amounts of sialic acid modifications.27PubMed. Erythropoietin produced in a human cell line (Dynepo) has significant differences in glycosylation compared with erythropoietins produced in CHO cell lines These glycosylation differences affect how long the drug lasts in the body, which is why the various EPO products on the market have different dosing schedules despite all being “the same” hormone.
An Evolutionary Footnote
The kidney’s dual role as both a blood-filtering organ and an oxygen sensor is not a coincidence unique to mammals. In rainbow trout, the kidney is not only a major site of blood cell production (fish lack the separate bone marrow that mammals have) but also the leading source of EPO in the body. Kidney tissue from these fish contained more immunoreactive EPO than plasma, spleen, or liver.28PubMed Central. Erythropoietin and the human kidney: evidence for an evolutionary link from studies of Salmo gairdneri The fact that the kidney has been coupled to EPO production across hundreds of millions of years of vertebrate evolution underscores how fundamental this organ’s oxygen-sensing function is. In mammals, the job of making red blood cells migrated to the bone marrow, but the kidney kept its role as the body’s EPO thermostat.