Caspase-11 promotes NLRP3 inflammasome activation via the cleavage of pannexinl in acute kidney disease

• 作者: Fan Yin Pei-qing Zheng Liu-qi Zhao Yan-zhe Wang Nai-jun Miao Zhuan-li Zhou Qian Cheng Pan-pan Chen Hong-yan Xie Jing-yao Li Jia-yun Ni Li Zhou Wei Zhang Xiao-xia Wang Jun Liu Li-min Lu
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2022,（1）
• 所属期刊栏目: Renal Pharmacology
• 页码范围: 86-95
• 页数: 10页
• 语种: 英文

摘要

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 l/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-1 β(IL-1β)maturation.In Casp-11-/-mice,l/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-1βmaturation 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.