Erythropoietin Secretion
Erythropoietin is primarily secreted by specialized interstitial fibroblastic cells (peritubular fibroblasts) in the renal cortex, which account for 90-95% of production in adults, with minor contributions from the liver, spleen, lungs, testicles, and brain. 1
Primary Production Site: The Kidney
Cellular Source in Adults
- Peritubular interstitial fibroblasts located in the cortical labyrinth of the kidney are the main cellular source of erythropoietin in adults 1, 2, 3
- These specialized fibroblasts are positioned in the angles between adjacent tubules or between tubules and vessels in the peritubular space 3
- Under normal conditions, erythropoietin mRNA is also expressed in proximal convoluted tubules, distal convoluted tubules, and cortical collecting ducts (particularly β-intercalated or non-α/non-β intercalated cells), though to a lesser extent 4
Response to Hypoxia
- During hypoxic conditions or anemia, erythropoietin production shifts predominantly to peritubular fibroblasts, with only slight increases in tubular production 4
- This suggests different regulatory mechanisms between nephron cells and peritubular cells under varying oxygen conditions 4
Secondary Production Sites
The Liver
- Hepatocytes and perisinusoidal Ito cells (hepatic stellate cells) produce erythropoietin, particularly during fetal life 2, 5
- The liver serves as a backup production site in adults, though it contributes minimally under normal circumstances 1
Other Tissues
- Small amounts are produced in the spleen, lungs, testicles, and brain 1
- These extrarenal sites become more relevant in patients with advanced kidney disease who have lost renal production capacity 1
Regulation of Secretion
Oxygen-Sensing Mechanism
- Hypoxia-inducible factor (HIF) is the master regulator, binding to the 3' enhancer region of the EPO gene to stimulate transcription in response to low tissue oxygen 1, 6
- The peritubular cells in the kidney are ideally positioned to sense oxygen delivery, as oxygen extraction is relatively high compared with oxygen delivery in this region 7
- A negative feedback system controls erythropoiesis: chronic hypoxemia stimulates erythropoietin production, which increases red blood cell mass and oxygen-carrying capacity 7
Clinical Implications
Chronic Kidney Disease
- Patients with chronic kidney disease develop anemia primarily because their kidneys lose the capacity for adequate endogenous erythropoietin production 1
- These patients require exogenous erythropoietin (epoetin) therapy to maintain adequate red blood cell production 1
Renal Transplantation
- Following successful kidney transplantation, erythropoietin production by the transplanted kidney is often delayed for 8-30 days 1
- Full correction of anemia may not occur for 2-3 months after surgery as the new kidney establishes adequate production 1
Renin-Producing Cells
- Recent experimental evidence suggests that renin-producing cells in the juxtaglomerular apparatus may also have erythropoietin biosynthetic capacity, which may explain transient childhood anemia in patients with REN mutations 7