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

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Mechanisms of hypoxia signalling: new implications for nephrology

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

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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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Background
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Additional file 12 of Hypoxia induces alterations in tRNA modifications involved in translational control
Guo, H., Lin, X., Wang, W., Xu, W., Shen, X., Wu, X., He, T., Jiang, X., Xu, Y., Zhao, P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22600426
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Additional file 8 of Hypoxia induces alterations in tRNA modifications involved in translational control
Guo, H., Xia, L., Wang, W., Xu, W., Shen, X., Wu, X., He, T., Jiang, X., Xu, Y., Zhao, P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22600414
Additional file 7 of Hypoxia induces alterations in tRNA modifications involved in translational control
Guo, H., Xia, L., Wang, W., Xu, W., Shen, X., Wu, X., He, T., Jiang, X., Xu, Y., Zhao, P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22600411
Additional file 2 of Hypoxia induces alterations in tRNA modifications involved in translational control
Guo, H., Xia, L., Wang, W., Xu, W., Shen, X., Wu, X., He, T., Jiang, X., Xu, Y., Zhao, P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22600387
Additional file 4 of Hypoxia induces alterations in tRNA modifications involved in translational control
Guo, H., Xia, L., Wang, W., Xu, W., Shen, X., Wu, X., He, T., Jiang, X., Xu, Y., Zhao, P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22600396
Additional file 6 of Hypoxia induces alterations in tRNA modifications involved in translational control
Guo, H., Xia, L., Wang, W., Xu, W., Shen, X., Wu, X., He, T., Jiang, X., Xu, Y., Zhao, P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22600405
Additional file 5 of Hypoxia induces alterations in tRNA modifications involved in translational control
Guo, H., Xia, L., Wang, W., Xu, W., Shen, X., Wu, X., He, T., Jiang, X., Xu, Y., Zhao, P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22600402
Additional file 3 of Hypoxia induces alterations in tRNA modifications involved in translational control
Guo, H., Xia, L., Wang, W., Xu, W., Shen, X., Wu, X., He, T., Jiang, X., Xu, Y., Zhao, P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22600390
Additional file 9 of Hypoxia induces alterations in tRNA modifications involved in translational control
Guo, H., Xia, L., Wang, W., Xu, W., Shen, X., Wu, X., He, T., Jiang, X., Xu, Y., Zhao, P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22600417
Additional file 1 of Hypoxia induces alterations in tRNA modifications involved in translational control
Guo, H., Xia, L., Wang, W., Xu, W., Shen, X., Wu, X., He, T., Jiang, X., Xu, Y., Zhao, P., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22600378
Lipopolysaccharide induces HIF-1α accumulation via MAPK p38–mediated mRNA stabilization and dexamethasone-sensitive protein stabilization
Lockwood, C., Daley, K. K., O’Neil, J. D., Heighes, K. J., Clayton, S. A., & Clark, A. R. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.111094
“The hypoxia-inducible transcription factor 1 α (HIF-1 α ) plays a central role in cellular adaptation to oxygen insufficiency, coordinating profound metabolic changes to ensure continued generation of ATP when mitochondrial function is impaired (1, 2).”

Authors: Schödel, J., & Ratcliffe, P. J.
Affiliations: Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
The Francis Crick Institute (GB)
Corresponding author: Ratcliffe, Peter J.
ORCID: Schödel, Johannes
Ratcliffe, Peter J.
Venue: Nature Reviews Nephrology
Publisher: Springer Science and Business Media LLC
Published: 2019-09-05
Volume: 15
Issue: 10
Pages: 641-659
ISSN: 1745-8323 (ISSN-L)
1759-5061
1759-507X
DOI: 10.1038/s41581-019-0182-z
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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Mechanisms of hypoxia signalling: new implications for nephrology

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