Erythropoietin (EPO) is produced primarily by which cells, and what is the primary stimulus for its production?

• A Juxtaglomerular cells of the kidney; stimulus is reduced renal blood flow
• B Hepatocytes exclusively; stimulus is anemia detected by bone marrow sinusoid pressure
• C Peritubular interstitial fibroblasts of the renal cortex and outer medulla; primary stimulus is tissue hypoxia sensed through HIF-1α/HIF-2α stabilization ✓
• D CD34+ stem cells of the bone marrow; EPO is produced locally in the marrow microenvironment

Explanation

EPO is produced predominantly (90%) by peritubular interstitial fibroblasts (type I fibrocytes) in the renal cortex and outer medulla. The key stimulus is hypoxia: reduced O2 delivery stabilizes HIF-2α (hypoxia-inducible factor-2α, the primary isoform driving EPO), which translocates to the nucleus, binds hypoxia response elements (HREs) in the EPO gene, and drives transcription. At normoxia, prolyl hydroxylase domain (PHD) enzymes hydroxylate HIF-2α, marking it for VHL-mediated proteasomal degradation. The liver produces ~10% of EPO (important in anephric patients who retain some EPO response). This pathway is targeted by PHD inhibitors (roxadustat) for renal anemia treatment.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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Written and medically reviewed by the StethoPrep medical team.