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.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:90001 |
| Date | 01 March 2024 |
| Creators | Tonnus, Wulf, Maremonti, Francesca, Belavgeni, Alexia, Latk, Markus, Kusunoki, Yoshihiro, Brucker, Anne, von Mässenhausen, Anne, Meyer, Claudia, Locke, Sophie, Gembardt, Florian, Beer, Kristina, Hoppenz, Paul, Becker, Jan U., Hugo, Christian, Anders, Hans-Joachim, Bornstein, Stefan R., Shao, Feng, Linkermann, Andreas |
| Publisher | Nature Publishing Group |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 2041-4889, 792, 10.1038/s41419-022-05230-9 |
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