Cited by 313Erythropoietin and Anemia TreatmentCancer, Hypoxia, and MetabolismAcute Kidney Injury Research

Mechanisms of hypoxia signalling: new implications for nephrology

Schödel, Johannes, Ratcliffe, Peter J.·2019·Nature Reviews Nephrology

Abstract

Studies of the regulation of erythropoietin (EPO) production by the liver and kidneys, one of the classical physiological responses to hypoxia, led to the discovery of human oxygen-sensing mechanisms, which are now being targeted therapeutically. The oxygen-sensitive signal is generated by 2-oxoglutarate-dependent dioxygenases that deploy molecular oxygen as a co-substrate to catalyse the post-translational hydroxylation of specific prolyl and asparaginyl residues in hypoxia-inducible factor (HIF), a key transcription factor that regulates transcriptional responses to hypoxia. Hydroxylation of HIF at different sites promotes both its degradation and inactivation. Under hypoxic conditions, these processes are suppressed, enabling HIF to escape destruction and form active transcriptional complexes at thousands of loci across the human genome. Accordingly, HIF prolyl hydroxylase inhibitors stabilize HIF and stimulate expression of HIF target genes, including the EPO gene. These molecules activate endogenous EPO gene expression in diseased kidneys and are being developed, or are already in clinical use, for the treatment of renal anaemia. In this Review, we summarize information on the molecular circuitry of hypoxia signalling pathways underlying these new treatments and highlight some of the outstanding questions relevant to their clinical use.

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Crossref · 10.1038/s41581-019-0182-z

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Authors
Schödel, J., & Ratcliffe, P. J.
Affiliations
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • The Francis Crick Institute (GB)
Corresponding author
Ratcliffe, Peter J.
Venue
Nature Reviews Nephrology
Published
2019-09-05
Volume
15
Issue
10
Pages
641-659
ISSN
  • 1745-8323 (ISSN-L)
  • 1759-5061
  • 1759-507X
OpenAlex
W2971880737
Cited by
309
References
255
Citations by year
2026: 22 · 2025: 36 · 2024: 48 · 2023: 64 · 2022: 53 · 2021: 54 · 2020: 31 · 2019: 1
FWCI
5.53
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Reviews Nephrology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Wellcome Trust (FC001501)
  • Cancer Research UK (FC001501)
  • British Heart Foundation (RG/11/1/28684)
Topics
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
Keywords
hypoxia signaling, hypoxia-inducible factor, prolyl hydroxylase inhibitors, erythropoietin, anemia of chronic kidney disease, 2-oxoglutarate-dependent dioxygenase, oxygen sensing, kidney disease, HIF target genes
MeSH terms
Animals, Hypoxia, Humans, Kidney, Kidney Diseases, Hypoxia-Inducible Factor 1

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