Gasdermin E deficiency attenuates acute kidney injury by inhibiting pyroptosis and inflammation.
Gasdermin E deficiency attenuates acute kidney injury by inhibiting pyroptosis and inflammation.
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Gasdermin E 缺乏通过抑制细胞焦亡和炎症来减轻急性肾损伤
DOI：
10.1038/s41419-021-03431-2
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发表时间：
2021-02-01
影响因子：
9
通讯作者：
Jia Z
中科院分区：
文献类型：
--
作者：
Xia W;Li Y;Wu M;Jin Q;Wang Q;Li S;Huang S;Zhang A;Zhang Y;Jia Z
细胞凋亡是一种炎症调节的细胞死亡，与包括急性肾损伤（阿基）在内的多种炎症性疾病有关。除了Gasdermin D（GSDMD）之外，GSDME是一种新鉴定的通过切割半胱天冬酶-3产生焦亡GSDME-N的焦亡介质。在这里，我们研究了GSDME在肾细胞焦亡和阿基发病机制中的作用，采用GSDME缺陷小鼠和人肾小管上皮细胞（TEC）与药理学和遗传学方法的干预。顺铂处理后，GSDME-N表达上调，IL-1β和LDH释放增加，细胞活力降低，GSDME-N介导的细胞凋亡被诱导，如特征性的细胞凋亡形态所示。引人注目的是，沉默小鼠中的GSDME减轻了急性肾损伤和炎症。GSDME的致热作用也在体外人TEC中得到验证。进一步的研究表明，抑制caspase-3阻断GSDME-N切割和减轻顺铂诱导的焦亡和肾功能不全。此外，GSDME的缺失也对缺血再灌注引起的肾损伤具有保护作用。总之，目前研究的结果表明，caspase-3/GSDME触发的焦亡和炎症有助于阿基，为理解和治疗这种疾病提供了新的见解。
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.
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影响因子：
3.7
作者：
Chung SD;Lai TY;Chien CT;Yu HJ
通讯作者：
Yu HJ
Caspase-3 介导的 GSDME 激活导致顺铂和阿霉素诱导的小鼠巨噬细胞继发性坏死
影响因子：
8.5
作者：
Mai, Feng-Yi;He, Pengyan;Hu, Bo
通讯作者：
Hu, Bo
影响因子：
8
作者：
Kim, M. S.;Chang, X.;Sidransky, D.
通讯作者：
Sidransky, D.
影响因子：
19.6
作者：
See, Emily J.;Jayasinghe, Kushani;Bellomo, Rinaldo
通讯作者：
Bellomo, Rinaldo
DOI：
10.1152/ajprenal.00104.2018
发表时间：
2018-09-01
影响因子：
4.2
作者：
Privratsky, Jamie R.;Zhang, Jiandong;Crowley, Steven D.
通讯作者：
Crowley, Steven D.