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

doi:10.1038/s41419-022-05230-9

Gasdermin D-deficient mice are hypersensitive to acute kidney injury

Cell Death Dis. 2022 Sep 15;13(9):792. doi: 10.1038/s41419-022-05230-9.

Authors

Wulf Tonnus^{1

2}, Francesca Maremonti^{1

2}, Alexia Belavgeni^{1

2}, Markus Latk^{1

2}, Yoshihiro Kusunoki³, Anne Brucker^{1

2}, Anne von Mässenhausen^{1

2}, Claudia Meyer^{1

2}, Sophie Locke^{1

2}, Florian Gembardt¹, Kristina Beer^{1

2}, Paul Hoppenz^{1

2}, Jan U Becker⁴, Christian Hugo¹, Hans-Joachim Anders³, Stefan R Bornstein^{1

5

6

7

8}, Feng Shao⁹, Andreas Linkermann^{10

11}

Affiliations

¹ Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
² Biotechnology Center, Technische Universität Dresden, Dresden, Germany.
³ Renal Division, Department of Medicine IV, University Hospital of the Ludwig Maximilian University, Munich, Germany.
⁴ Institute of Pathology, University Hospital of Cologne, Cologne, Germany.
⁵ Diabetes and Nutritional Sciences, King's College London, London, UK.
⁶ Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany.
⁷ Paul Langerhans Institute Dresden of Helmholtz Centre Munich at University Clinic Carl Gustav Carus of TU Dresden Faculty of Medicine, Dresden, Germany.
⁸ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
⁹ National Institute of Biological Sciences (NIBS), Beijing, China.
¹⁰ Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany. andreas.linkermann@ukdd.de.
¹¹ Biotechnology Center, Technische Universität Dresden, Dresden, Germany. andreas.linkermann@ukdd.de.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Kidney Injury* / metabolism
Animals
Cisplatin / adverse effects
Creatinine
Hypersensitivity*
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Mice
Phosphate-Binding Proteins / genetics
Phosphate-Binding Proteins / metabolism
Urea

Substances

Intracellular Signaling Peptides and Proteins
Phosphate-Binding Proteins
Urea
Creatinine
Cisplatin