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.

Key points

  • Hypoxia-inducible factors (HIFs) transduce transcriptional responses to hypoxia that involve hundreds to thousands of target genes.

  • The oxygen-sensitive signal regulating HIF activity is generated by 2-oxoglutarate-dependent dioxygenases that catalyse the hydroxylation of specific HIF prolyl and asparaginyl residues to inactivate HIF in the presence of oxygen.

  • Inhibition of the HIF prolyl hydroxylases by 2-oxoglutarate analogues mimics hypoxia and activates many, but not all, components of the HIF transcriptional response.

  • Erythropoietin production by cortical interstitial fibroblasts in the kidney is very sensitive to activation of the HIF pathway.

  • In diseased kidneys, erythropoietin production is reduced, but can be increased by HIF prolyl hydroxylase inhibitors.

  • Activation of HIF has the potential to generate many other renal and systemic effects that will require consideration when HIF prolyl hydroxylase inhibitors are used clinically.

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Fig. 1: General mechanism of oxidation catalysed by 2-oxoglutarate-dependent dioxygenases
Fig. 2: Regulation of HIF-1α and HIF-2α.
Fig. 3: Feedback mechanisms of hypoxic gene regulation.
Fig. 4: HIF isoform expression profiles and target gene selectivity.
Fig. 5: Erythropoietin regulation in normal and diseased kidneys.
Fig. 6: Actions of HIF in the kidney.

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Acknowledgements

The authors thank E. Flashman, University of Oxford, for assistance in preparing figure 1. P.J.R.’s laboratory is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001501), the UK Medical Research Council (FC001501) and the Wellcome Trust (FC001501). P.J.R. is a Wellcome Trust Senior Investigator and a member of the Ludwig Institute for Cancer Research. J.S. was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; Projektnummer 387509280; SFB 1350).

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Both authors contributed equally to this manuscript.

Correspondence to Peter J. Ratcliffe.

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Competing interests

P.J.R. is a scientific co-founder of ReOx Ltd., an Oxford University spin-out company that seeks to promote the therapeutic development of prolyl hydroxylase inhibitors. P.J.R. has served as a member of GlaxoSmithKline’s Research Advisory Board and holds equity in the company. J.S. declares no competing interests.

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Peer review informationNature Reviews Nephrology thanks J. Myllyharju and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Schödel, J., Ratcliffe, P.J. Mechanisms of hypoxia signalling: new implications for nephrology. Nat Rev Nephrol 15, 641–659 (2019). https://doi.org/10.1038/s41581-019-0182-z

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