Erythropoietin (EPO) is produced by peritubular interstitial cells of the kidney in response to hypoxia. The HIF (Hypoxia Inducible Factor) pathway that mediates EPO gene transcription involves:

• A Under normoxia, PHD hydroxylates HIF-1alpha → VHL-mediated ubiquitination → proteasomal degradation; hypoxia inhibits PHD, allowing HIF-1alpha accumulation ✓
• B HIF-1alpha is constitutively stable and continuously drives EPO gene expression
• C Hypoxia directly increases EPO mRNA transcription via a heat shock factor
• D HIF-2alpha is the predominant isoform for non-renal EPO regulation in the liver

Explanation

Under normoxia, prolyl hydroxylase domain enzymes (PHDs) hydroxylate HIF-1alpha at specific proline residues using O2, iron, and alpha-ketoglutarate as co-substrates. Hydroxylated HIF-1alpha is recognised by the VHL E3 ubiquitin ligase, leading to polyubiquitination and proteasomal degradation. During hypoxia, O2 deficiency inhibits PHDs, allowing HIF-1alpha to accumulate, dimerise with HIF-1beta, and transactivate hypoxia-response element (HRE)-containing genes including EPO. HIF-2alpha is actually the dominant isoform regulating renal EPO synthesis.

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

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