HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism

Hemodial Int. 2017 Jun;21 Suppl 1(Suppl 1):S110-S124. doi: 10.1111/hdi.12567.

Abstract

A classic response to systemic hypoxia is the increase in red blood cell production. This response is controlled by the prolyl hydroxylase domain/hypoxia-inducible factor (HIF) pathway, which regulates a broad spectrum of cellular functions. The discovery of this pathway as a key regulator of erythropoiesis has led to the development of small molecules that stimulate the production of endogenous erythropoietin and enhance iron metabolism. This review provides a concise overview of the cellular and molecular mechanisms that govern HIF-induced erythropoietic responses and provides an update on clinical experience with compounds that target HIF-prolyl hydroxylases for anemia therapy.

Keywords: Anemia; erythropoietin; hypoxia-inducible factor; iron; prolyl hydroxylase.

Publication types

  • Review

MeSH terms

  • Anemia / drug therapy
  • Barbiturates / adverse effects
  • Barbiturates / therapeutic use
  • Clinical Trials as Topic
  • Erythropoiesis / drug effects*
  • Erythropoietin / biosynthesis
  • Glycine / adverse effects
  • Glycine / analogs & derivatives
  • Glycine / therapeutic use
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases / physiology*
  • Iron / metabolism*
  • Isoquinolines / adverse effects
  • Isoquinolines / therapeutic use
  • Picolinic Acids / adverse effects
  • Picolinic Acids / therapeutic use
  • Prolyl-Hydroxylase Inhibitors / therapeutic use*
  • Renal Dialysis / adverse effects

Substances

  • Barbiturates
  • EPO protein, human
  • FG-4592
  • GSK1278863
  • Isoquinolines
  • Picolinic Acids
  • Prolyl-Hydroxylase Inhibitors
  • vadadustat
  • Erythropoietin
  • Iron
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Glycine