@article{APS10458,
author = {Fan Yin and Pei-qing Zheng and Liu-qi Zhao and Yan-zhe Wang and Nai-jun Miao and Zhuan-li Zhou and Qian Cheng and Pan-pan Chen and Hong-yan Xie and Jing-yao Li and Jia-yun Ni and Li Zhou and Wei Zhang and Xiao-xia Wang and Jun Liu and Li-min Lu},
title = {Caspase-11 promotes NLRP3 inflammasome activation via the cleavage of pannexin1 in acute kidney disease},
journal = {Acta Pharmacologica Sinica},
volume = {43},
number = {1},
year = {2021},
keywords = {},
abstract = {Ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI) in clinic. The activation of NLRP3 inflammasome is associated with inflammation and renal injury in I/R-induced AKI. In the current study we explored the molecular and cellular mechanisms for NLRP3 inflammasome activation following renal I/R. Mice were subjected to I/R renal injury by clamping bilateral renal pedicles. We showed that I/R injury markedly increased caspase-11 expression and the cleavage of pannexin 1 (panx1) in the kidneys accompanied by NLRP3 inflammasome activation evidenced by the activation of caspase-1 and interlukin-1β (IL-1β) maturation. In Casp-11−/− mice, I/R-induced panx1 cleavage, NLRP3 inflammasome activation as well as renal functional deterioration and tubular morphological changes were significantly attenuated. In cultured primary tubular cells (PTCs) and NRK- 52E cells, hypoxia/reoxygenation (H/R) markedly increased caspase-11 expression, NLRP3 inflammasome activation, IL-1β maturation and panx1 cleavage. Knockdown of caspase-11 attenuated all those changes; similar effects were observed in PTCs isolated from Casp-11−/− mice. In NRK-52E cells, overexpression of caspase-11 promoted panx1 cleavage; pretreatment with panx1 inhibitor carbenoxolone or knockdown of panx1 significantly attenuated H/R-induced intracellular ATP reduction, extracellular ATP elevation and NLRP3 inflammasome activation without apparent influence on H/R-induced caspase-11 increase; pretreatment with P2X7 receptor inhibitor AZD9056 also attenuated NLRP3 inflammasome activation. The above results demonstrate that the cleavage of panx1 by upregulated caspase-11 is involved in facilitating ATP release and then NLRP3 inflammasome activation in I/R- induced AKI. This study provides new insight into the molecular mechanism of NLRP3 inflammasome activation in AKI.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/10458}
}