Erythropoietin (EPO) is primarily produced in the kidney in response to hypoxia. The intracellular mechanism by which hypoxia triggers EPO gene transcription is:

• A Low PO2 directly activates JAK2 on EPO receptor-expressing peritubular cells, upregulating EPO gene expression via STAT5
• B Hypoxia activates AMPK, which phosphorylates HIF-1beta, enabling it to drive EPO transcription
• C Reduced renal cortical blood flow activates the renin-angiotensin system, and angiotensin II directly upregulates EPO gene expression
• D Hypoxia stabilises HIF-1alpha (hypoxia-inducible factor 1-alpha) by preventing prolyl-hydroxylase (PHD)-mediated hydroxylation, VHL-binding, and proteasomal degradation; HIF-1alpha translocates to the nucleus and activates EPO gene transcription via HREs ✓

Explanation

EPO production is regulated by the HIF (hypoxia-inducible factor) pathway. Under normoxia, prolyl hydroxylases (PHDs) use O2 and alpha-ketoglutarate to hydroxylate specific proline residues (Pro402, Pro564) on HIF-1alpha. Hydroxylated HIF-1alpha is recognised by the VHL E3 ubiquitin ligase complex, ubiquitinated, and degraded by the proteasome. Under hypoxia, O2 is limiting, PHDs are inactive, HIF-1alpha is not hydroxylated and escapes degradation. It accumulates, translocates to the nucleus, dimerises with the constitutively expressed HIF-1beta (ARNT) subunit, and the HIF-1 complex binds hypoxia-response elements (HREs; consensus 5'-RCGTG-3') in the EPO gene promoter/enhancer, dramatically increasing EPO transcription. This is also the basis of HIF-prolyl hydroxylase inhibitors (e.g., roxadustat) used in CKD anaemia. Options B–D are incorrect mechanisms.

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

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Written and medically reviewed by the StethoPrep medical team.