Gasdermin D-deficient mice are hypersensitive to acute kidney injury
Abstract Signaling pathways of regulated necrosis, such as necroptosis and ferroptosis, contribute to acute kidney injury (AKI), but the role of pyroptosis is unclear. Pyroptosis is mediated by the pore-forming protein gasdermin D (GSDMD). Here, we report a specific pattern of GSDMD-protein expressi...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-09-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05230-9 |
| _version_ | 1798000741118377984 |
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| author | Wulf Tonnus Francesca Maremonti Alexia Belavgeni Markus Latk Yoshihiro Kusunoki Anne Brucker Anne von Mässenhausen Claudia Meyer Sophie Locke Florian Gembardt Kristina Beer Paul Hoppenz Jan U. Becker Christian Hugo Hans-Joachim Anders Stefan R. Bornstein Feng Shao Andreas Linkermann |
| author_facet | Wulf Tonnus Francesca Maremonti Alexia Belavgeni Markus Latk Yoshihiro Kusunoki Anne Brucker Anne von Mässenhausen Claudia Meyer Sophie Locke Florian Gembardt Kristina Beer Paul Hoppenz Jan U. Becker Christian Hugo Hans-Joachim Anders Stefan R. Bornstein Feng Shao Andreas Linkermann |
| author_sort | Wulf Tonnus |
| collection | DOAJ |
| description | Abstract Signaling pathways of regulated necrosis, such as necroptosis and ferroptosis, contribute to acute kidney injury (AKI), but the role of pyroptosis is unclear. Pyroptosis is mediated by the pore-forming protein gasdermin D (GSDMD). Here, we report a specific pattern of GSDMD-protein expression in the peritubular compartment of mice that underwent bilateral ischemia and reperfusion injury (IRI). Along similar lines, the GSDMD-protein expression in whole kidney lysates increased during the first 84 h following cisplatin-induced AKI. Importantly, unlike whole kidney lysates, no GSDMD-protein expression was detectable in isolated kidney tubules. In IRI and cisplatin-induced AKI, GSDMD-deficient mice exhibited hypersensitivity to injury as assessed by tubular damage, elevated markers of serum urea, and serum creatinine. This hypersensitivity was reversed by a combined deficiency of GSDMD and the necroptosis mediator mixed lineage kinase domain-like (MLKL). In conclusion, we demonstrate a non-cell autonomous role for GSDMD in protecting the tubular compartment from necroptosis-mediated damage in IRI. |
| first_indexed | 2024-04-11T11:25:12Z |
| format | Article |
| id | doaj.art-c8cee3d8b1414230892321cb893adef0 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-11T11:25:12Z |
| publishDate | 2022-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-c8cee3d8b1414230892321cb893adef02022-12-22T04:26:20ZengNature Publishing GroupCell Death and Disease2041-48892022-09-0113911010.1038/s41419-022-05230-9Gasdermin D-deficient mice are hypersensitive to acute kidney injuryWulf Tonnus0Francesca Maremonti1Alexia Belavgeni2Markus Latk3Yoshihiro Kusunoki4Anne Brucker5Anne von Mässenhausen6Claudia Meyer7Sophie Locke8Florian Gembardt9Kristina Beer10Paul Hoppenz11Jan U. Becker12Christian Hugo13Hans-Joachim Anders14Stefan R. Bornstein15Feng Shao16Andreas Linkermann17Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenDepartment of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenDepartment of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenDepartment of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenRenal Division, Department of Medicine IV, University Hospital of the Ludwig Maximilian UniversityDepartment of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenDepartment of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenDepartment of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenDepartment of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenDepartment of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenDepartment of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenDepartment of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenInstitute of Pathology, University Hospital of CologneDepartment of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenRenal Division, Department of Medicine IV, University Hospital of the Ludwig Maximilian UniversityDepartment of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenNational Institute of Biological Sciences (NIBS)Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität DresdenAbstract Signaling pathways of regulated necrosis, such as necroptosis and ferroptosis, contribute to acute kidney injury (AKI), but the role of pyroptosis is unclear. Pyroptosis is mediated by the pore-forming protein gasdermin D (GSDMD). Here, we report a specific pattern of GSDMD-protein expression in the peritubular compartment of mice that underwent bilateral ischemia and reperfusion injury (IRI). Along similar lines, the GSDMD-protein expression in whole kidney lysates increased during the first 84 h following cisplatin-induced AKI. Importantly, unlike whole kidney lysates, no GSDMD-protein expression was detectable in isolated kidney tubules. In IRI and cisplatin-induced AKI, GSDMD-deficient mice exhibited hypersensitivity to injury as assessed by tubular damage, elevated markers of serum urea, and serum creatinine. This hypersensitivity was reversed by a combined deficiency of GSDMD and the necroptosis mediator mixed lineage kinase domain-like (MLKL). In conclusion, we demonstrate a non-cell autonomous role for GSDMD in protecting the tubular compartment from necroptosis-mediated damage in IRI.https://doi.org/10.1038/s41419-022-05230-9 |
| spellingShingle | Wulf Tonnus Francesca Maremonti Alexia Belavgeni Markus Latk Yoshihiro Kusunoki Anne Brucker Anne von Mässenhausen Claudia Meyer Sophie Locke Florian Gembardt Kristina Beer Paul Hoppenz Jan U. Becker Christian Hugo Hans-Joachim Anders Stefan R. Bornstein Feng Shao Andreas Linkermann Gasdermin D-deficient mice are hypersensitive to acute kidney injury Cell Death and Disease |
| title | Gasdermin D-deficient mice are hypersensitive to acute kidney injury |
| title_full | Gasdermin D-deficient mice are hypersensitive to acute kidney injury |
| title_fullStr | Gasdermin D-deficient mice are hypersensitive to acute kidney injury |
| title_full_unstemmed | Gasdermin D-deficient mice are hypersensitive to acute kidney injury |
| title_short | Gasdermin D-deficient mice are hypersensitive to acute kidney injury |
| title_sort | gasdermin d deficient mice are hypersensitive to acute kidney injury |
| url | https://doi.org/10.1038/s41419-022-05230-9 |
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