Elsevier

Kidney International

Volume 96, Issue 5, November 2019, Pages 1105-1120
Kidney International

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

https://doi.org/10.1016/j.kint.2019.04.035Get rights and content
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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

caspase-11
gasdermin D
interleukin-18
acute kidney injury

Cited by (0)

4

NM and FY are co-first authors.