Caspase-11 promotes NLRP3 inflammasome activation via the cleavage of pannexin1 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 

机构地区：[1]Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Fudan University,Shanghai,200032,China [2]Department of Nephrology,Shanghai Tong Ren Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,200336,China [3]Shanghai Kidney Development and Pediatric Kidney Disease Research Center,Shanghai,201102,China

出　　处：《Acta Pharmacologica Sinica》2022年第1期86-95,共10页中国药理学报（英文版）

基　　金：This research was financially supported by the National Natural Science Foundation of China(No.82070712,81873603,81670664)to LML,and(No.81873603)to XXW.The authors would like to thank the research participants for volunteering their time in the study.

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 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-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.

关 键 词：acute kidney injury ischemia/reperfusion injury caspase-11 NLRP3 inflammasome pannexin 1 P2X7 receptor ATP primary tubular cells NRK-52E cells CARBENOXOLONE AZD9056 

分 类 号：R96[医药卫生—药理学] R692[医药卫生—药学]