GSDME-mediated pyroptosis promotes inflammation and fibrosis in obstructive nephropathy.
Yinshuang Li,Ying Yuan,Zhong-Xing Huang,Hui Chen,Ruilong Lan,Zeng Wang,Kunmei Lai,Hong Chen,Zhimin Chen,Zhenhuan Zou,Hua-Bin Ma,Hui-Yao Lan,Tak W. Mak,Tak W. Mak,Yanfang Xu +14 more
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TLDR
In this paper, the authors showed that TNFα/Casp3/GSDME-mediated pyroptosis is responsible for the initiation of ureteral obstruction-induced renal tubule injury, which subsequentially contributes to the late stage progression of hydronephrosis, inflammation and fibrosis.Abstract:
Renal tubular cell (RTC) death and inflammation contribute to the progression of obstructive nephropathy, but its underlying mechanisms have not been fully elucidated. Here, we showed that Gasdermin E (GSDME) expression level and GSDME-N domain generation determined the RTC fate response to TNFα under the condition of oxygen-glucose-serum deprivation. Deletion of Caspase-3 (Casp3) or Gsdme alleviated renal tubule damage and inflammation and finally prevented the development of hydronephrosis and kidney fibrosis after ureteral obstruction. Using bone marrow transplantation and cell type-specific Casp3 knockout mice, we demonstrated that Casp3/GSDME-mediated pyroptosis in renal parenchymal cells, but not in hematopoietic cells, played predominant roles in this process. We further showed that HMGB1 released from pyroptotic RTCs amplified inflammatory responses, which critically contributed to renal fibrogenesis. Specific deletion of Hmgb1 in RTCs alleviated caspase11 and IL-1β activation in macrophages. Collectively, our results uncovered that TNFα/Casp3/GSDME-mediated pyroptosis is responsible for the initiation of ureteral obstruction-induced renal tubule injury, which subsequentially contributes to the late-stage progression of hydronephrosis, inflammation, and fibrosis. This novel mechanism will provide valuable therapeutic insights for the treatment of obstructive nephropathy.read more
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References
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Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death
Jianjin Shi,Yue Zhao,Kun Wang,Xuyan Shi,Wang Yue,Huanwei Huang,Yinghua Zhuang,Tao Cai,Fengchao Wang,Feng Shao +9 more
TL;DR: Gasdermin D (Gsdmd) is identified by genome-wide clustered regularly interspaced palindromic repeat-Cas9 nuclease screens of caspase-11- and caspasing-1-mediated pyroptosis in mouse bone marrow macrophages to offer insight into inflammasome-mediated immunity/diseases and change the understanding of pyroPTosis and programmed necrosis.
Journal ArticleDOI
Pore-forming activity and structural autoinhibition of the gasdermin family
Jingjin Ding,Kun Wang,Wang Liu,Yang She,Qi Sun,Jianjin Shi,Hanzi Sun,Da-Cheng Wang,Da-Cheng Wang,Feng Shao +9 more
TL;DR: It is demonstrated that the liposome-leakage and pore-forming activities of the gasdermin-N domain are required for pyroptosis and provide insights into the roles of theGasdermin family in necrosis, immunity and diseases.
Journal ArticleDOI
Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin
TL;DR: It is shown that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5), can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis, suggesting that casp enzyme activation can trigger necrosis by cleaving G SDME and offer new insights into cancer chemotherapy.
Journal ArticleDOI
Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion
Wan-ting He,Haoqiang Wan,Lichen Hu,Pengda Chen,Xin Wang,Zhe Huang,Zhang-Hua Yang,Chuan-Qi Zhong,Jiahuai Han +8 more
TL;DR: It is reported that gasdermin D (GSDMD) is another crucial component of inflammasomes and the presence of GSDMD protein in nigericin-induced NLRP3 inflammaomes is discovered by a quantitative mass spectrometry-based analysis.
Journal ArticleDOI
Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy
TL;DR: The UUO model is likely to reveal useful biomarkers of progression of renal disease, as well as new therapies, which are desperately needed to allow intervention before the establishment of irreversible renal injury.