Erythropoietin (EPO) is secreted primarily by the peritubular interstitial cells of the renal cortex. Its production is stimulated by hypoxia through which transcription factor pathway?

• A Hypoxia-inducible factor-1α (HIF-1α) stabilization when prolyl hydroxylase domain (PHD) enzymes are inhibited by low O2 ✓
• B NF-κB pathway activated by inflammatory cytokines
• C STAT3 pathway activated by interleukin-6
• D Wnt/β-catenin pathway in response to haem deficiency

Explanation

Under normoxia, HIF-1α is continuously hydroxylated by PHD enzymes (requiring O2 and α-ketoglutarate as cofactors), targeting it for von Hippel-Lindau (VHL) protein-mediated ubiquitination and proteasomal degradation. In hypoxia, PHD enzymes are inhibited, HIF-1α accumulates, dimerizes with HIF-1β, and translocates to the nucleus to transcribe the EPO gene (among others). PHD inhibitors (roxadustat, daprodustat) exploit this mechanism therapeutically to increase EPO in CKD-related anaemia.

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

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