The DOI matches its Crossref record; 255 of the 255 references it cites were found in a registry or an index.
Mechanisms of hypoxia signalling: new implications for 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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“HIFs are significantly upregulated in many cancer types, and the application of HIF inhibitors as anticancer therapies has captured great interest.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [150]
Citations
Cites
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Self-citationHIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
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A conserved family of prolyl-4-hydroxylases that modify HIF
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Self-citation
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Physiological roles of hydrogen sulfide in mammalian cells, tissues, and organs
Cirino, G., Szabó, C., & Papapetropoulos, A. (2022) · Physiological Reviews · doi:10.1152/physrev.00028.2021 · Cited by 578
The effect of HIF on metabolism and immunity
Taylor, C. T., & Scholz, C. C. (2022) · Nature Reviews Nephrology · doi:10.1038/s41581-022-00587-8 · Cited by 517
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“The mechanisms by which intracellular oxygen levels regulate HIF-1α have been well described and occur mainly at the protein level with smaller effects on mRNA expression (Ivan and Kaelin 2017; Schödel and Ratcliffe 2019; Semenza 2019).”
Background
Metadata
- 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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