2. Academic Validation
  3. The cleavage of gasdermin D by caspase-11 promotes tubular epithelial cell pyroptosis and urinary IL-18 excretion in acute kidney injury

The cleavage of gasdermin D by caspase-11 promotes tubular epithelial cell pyroptosis and urinary IL-18 excretion in acute kidney injury

  • Kidney Int. 2019 Nov;96(5):1105-1120. doi: 10.1016/j.kint.2019.04.035.
Naijun Miao 1,  Fan Yin 1,  Hongyan Xie 1,  Yanzhe Wang 2,  Yiang Xu 1,  Yang Shen 1,  Dan Xu 1,  Jianyong Yin 3,  Bao Wang 1,  Zhuanli Zhou 1,  Qian Cheng 1,  Panpan Chen 1,  Hong Xue 1,  Li Zhou 1,  Jun Liu 1,  Xiaoxia Wang 4,  Wei Zhang 5,  Limin Lu 6
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China.
  • 2 Department of Nephrology, Shanghai Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, China.
  • 3 Department of Nephrology and Rheumatology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 4 Department of Nephrology, Shanghai Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, China. Electronic address: [email protected].
  • 5 Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 6 Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China. Electronic address: [email protected].
PMID: 31405732 DOI: 10.1016/j.kint.2019.04.035
Abstract

Inflammation and tubular cell death are the hallmarks of acute kidney injury. However, the precise mechanism underlying these effects has not been fully elucidated. Here we tested whether caspase-11, an inflammatory member of the Caspase family, was increased in cisplatin or ischemia-reperfusion-induced acute kidney injury. Caspase-11 knockout mice after cisplatin treatment exhibited attenuated deterioration of renal functional, reduced tubular damage, reduced macrophage and neutrophil infiltration, and decreased urinary IL-18 excretion. Mechanistically, the upregulation of caspase-11 by either cisplatin or ischemia-reperfusion cleaved gasdermin D (GSDMD) into GSDMD-N, which translocated onto the plasma membrane, thus triggering cell Pyroptosis and facilitated IL-18 release in primary cultured renal tubular cells. These results were further confirmed in GSDMD knockout mice that cisplatin-induced renal morphological and functional deterioration as well as urinary IL-18 excretion were alleviated. Furthermore, deficiency of GSDMD significantly suppressed cisplatin-induced IL-18 release but not the transcription and maturation level of IL-18 in tubular cells. Thus, our study indicates that caspase-11/GSDMD dependent tubule cell Pyroptosis plays a significant role in initiating tubular cell damage, urinary IL-18 excretion and renal functional deterioration in acute kidney injury.

Keywords

acute kidney injury; caspase-11; gasdermin D; interleukin-18.

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