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.

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

Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Fudan University,Shanghai 200032,China;Department of Nephrology,Shanghai Tong Ren Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200336,China;Shanghai Kidney Development and Pediatric Kidney Disease Research Center,Shanghai 201102,China

中国药理学报（英文版）

[1]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-.Caspase-11 promotes NLRP3 inflammasome activation via the cleavage of pannexinl in acute kidney disease)[J].中国药理学报（英文版）,2022(01):86-95

pannexinl,pedicles,panx1,PTCs,carbenoxolone,AZD9056

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