Gasdermin D-deficient mice are hypersensitive to acute kidney injury

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

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.

Original languageEnglish
Article number792
JournalCell Death and Disease
Volume13
Issue number9
DOIs
Publication statusPublished - Sept 2022

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