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Gasdermins and pyroptosis in the kidney

Nature Reviews Nephrology volume 19, pages 337–350 (2023)Cite this article

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Abstract

Pyroptosis is a form of regulated cell death that is mediated by the membrane-targeting, pore-forming gasdermin family of proteins. Pyroptosis was initially described as a caspase 1- and inflammasome-dependent cell death pathway typified by the loss of membrane integrity and the secretion of cytokines such as IL-1β. However, gasdermins are now recognized as the principal effectors of this form of regulated cell death; activated gasdermins insert into cell membranes, where they form pores that result in the secretion of cytokines, alarmins and damage-associated molecular patterns and cause cell membrane rupture. It is now evident that gasdermins can be activated by inflammasome- and caspase-independent mechanisms in multiple cell types and that crosstalk occurs between pyroptosis and other cell death pathways. Although they are important for host antimicrobial defence, a growing body of evidence supports the notion that pyroptosis and gasdermins have pathological roles in cancer and several non-microbial diseases involving the gut, liver and skin. The well-documented roles of inflammasome activity and apoptosis pathways in kidney diseases suggests that gasdermins and pyroptosis may also be involved to some extent. However, despite some evidence for involvement of pyroptosis in the context of acute kidney injury and chronic kidney disease, our understanding of gasdermin biology and pyroptosis in the kidney remains limited.

Key points

  • Pyroptosis is a pro-inflammatory form of regulated cell death that is mediated by the gasdermin family of proteins.

  • The gasdermin family includes gasdermins A–E and pejvakin; the different family members are differentially expressed in tissues and are proteolytically activated by caspases and granzymes.

  • Activated gasdermins insert into cell membranes, where they form pores that result in the secretion of cytokines, the release of cellular alarmins and damage-associated molecular patterns, and cell membrane rupture.

  • Pyroptosis and gasdermins participate in host antimicrobial defence and in the pathogenesis of non-microbial diseases such as cancer, gastrointestinal disease and kidney disease.

  • The role of pyroptosis and gasdermins in kidney disease is under-studied and incompletely understood.

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Fig. 1: Canonical and non-canonical GSDMD regulation in leukocytes.
Fig. 2: Inflammasome-independent gasdermin regulation.
Fig. 3: Proposed mechanisms of pyroptosis in kidney diseases.

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Acknowledgements

The authors’ work was supported by the Canadian Institutes for Health Research. E.E.E. is funded by a Snyder Institute for Chronic Diseases Beverly-Phillips Fellowship.

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  1. Snyder Institute for Chronic Diseases, Department of Medicine, University of Calgary, Calgary, AB, Canada

    Esteban E. Elias, Brayden Lyons & Daniel A. Muruve

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E.E.E. and D.A.M researched data for the article, contributed substantially to discussion of the content and wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Elias, E.E., Lyons, B. & Muruve, D.A. Gasdermins and pyroptosis in the kidney. Nat Rev Nephrol 19, 337–350 (2023). https://doi.org/10.1038/s41581-022-00662-0

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