Gasdermin E deficiency attenuates acute kidney injury by inhibiting pyroptosis and inflammation

Pyroptosis, one kind of inflammatory regulated cell death, is involved in various inflammatory diseases, including acute kidney injury (AKI). Besides Gasdermin D (GSDMD), GSDME is a newly identified mediator of pyroptosis via the cleavage of caspase-3 generating pyroptotic GSDME-N. Here, we investig...

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Bibliographic Details
Published in:Cell death & disease 2021-02, Vol.12 (2), p.139-139, Article 139
Main Authors: Xia, Weiwei, Li, Yuanyuan, Wu, Mengying, Jin, Qianqian, Wang, Qian, Li, Shuzhen, Huang, Songming, Zhang, Aihua, Zhang, Yue, Jia, Zhanjun
Format: Article
Language:English
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Antibodies
Biochemistry
Biomedical and Life Sciences
Caspase-3
Cell Biology
Cell Culture
Cell death
Cell viability
Cisplatin
Epithelial cells
IL-1β
Immunology
Inflammation
Inflammatory diseases
Ischemia
Kidney diseases
Kidneys
Life Sciences
Physical characteristics
Pyroptosis
Reperfusion
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Summary:Pyroptosis, one kind of inflammatory regulated cell death, is involved in various inflammatory diseases, including acute kidney injury (AKI). Besides Gasdermin D (GSDMD), GSDME is a newly identified mediator of pyroptosis via the cleavage of caspase-3 generating pyroptotic GSDME-N. Here, we investigated the role of GSDME in renal cellular pyroptosis and AKI pathogenesis employing GSDME-deficient mice and human tubular epithelial cells (TECs) with the interventions of pharmacological and genetic approaches. After cisplatin treatment, GSDME-mediated pyroptosis was induced as shown by the characteristic pyroptotic morphology in TECs, upregulated GSDME-N expression and enhanced release of IL-1β and LDH, and decreased cell viability. Strikingly, silencing GSDME in mice attenuated acute kidney injury and inflammation. The pyroptotic role of GSDME was also verified in human TECs in vitro. Further investigation showed that inhibition of caspase-3 blocked GSDME-N cleavage and attenuated cisplatin-induced pyroptosis and kidney dysfunction. Moreover, deletion of GSDME also protected against kidney injury induced by ischemia-reperfusion. Taken together, the findings from current study demonstrated that caspase-3/GSDME-triggered pyroptosis and inflammation contributes to AKI, providing new insights into the understanding and treatment of this disease.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-021-03431-2