Regulation of Erythropoiesis by the Hypoxia-Inducible Factor Pathway: Effects of Genetic and Pharmacological Perturbations

Annu Rev Med. 2023 Jan 27:74:307-319. doi: 10.1146/annurev-med-042921-102602. Epub 2022 Jun 30.


Red blood cells transport O2 from the lungs to body tissues. Hypoxia stimulates kidney cells to secrete erythropoietin (EPO), which increases red cell mass. Hypoxia-inducible factors (HIFs) mediate EPO gene transcriptional activation. HIF-α subunits are subject to O2-dependent prolyl hydroxylation and then bound by the von Hippel-Lindau protein (VHL), which triggers their ubiquitination and proteasomal degradation. Mutations in the genes encoding EPO, EPO receptor, HIF-2α, prolyl hydroxylase domain protein 2 (PHD2), or VHL cause familial erythrocytosis. In addition to O2, α-ketoglutarate is a substrate for PHD2, and analogs of α-ketoglutarate inhibit hydroxylase activity. In phase III clinical trials evaluating the treatment of anemia in chronic kidney disease, HIF prolyl hydroxylase inhibitors were as efficacious as darbepoetin alfa in stimulating erythropoiesis. However, safety concerns have arisen that are focused on thromboembolism, which is also a phenotypic manifestation of VHL or HIF-2α mutation, suggesting that these events are on-target effects of HIF prolyl hydroxylase inhibitors.

Keywords: HIF prolyl hydroxylase inhibitor; chronic kidney disease; erythropoiesis-stimulating agent; erythropoietin; thromboembolism.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Erythropoiesis* / genetics
  • Humans
  • Hypoxia
  • Ketoglutaric Acids
  • Prolyl-Hydroxylase Inhibitors* / pharmacology
  • Prolyl-Hydroxylase Inhibitors* / therapeutic use


  • Prolyl-Hydroxylase Inhibitors
  • Ketoglutaric Acids
  • Basic Helix-Loop-Helix Transcription Factors