mROS-TXNIP axis activates NLRP3 inflammasome to mediate renal injury during ischemic AKI

• Published in: The international journal of biochemistry & cell biology Vol. 98; pp. 43 - 53
• Main Authors: Wen, Yi, Liu, Yi-Ran, Tang, Tao-Tao, Pan, Ming-Ming, Xu, Sheng-Chun, Ma, Kun-Ling, Lv, Lin-Li, Liu, Hong, Liu, Bi-Cheng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.05.2018
• Subjects: Ischemic AKI; Mitochondrial dysfunction; NLRP3 inflammasome; TXNIP; MCP-1; Mitochondrial dysfunction; IL-1β; NLRP3 inflammasome; I/R; ASC; NAC; TEC; TNF-α; Ischemic AKI; ROS; NLRP3; TXNIP
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/j.biocel.2018.02.015

Ischemia/reperfusion (I/R) is a critical risk factor for acute kidney injury (AKI). Recent studies provided evidence that tubular epithelial cells (TEC)-associated inflammation aggravates kidney injury and impairs tissue repair after I/R injury. Here we demonstrated that the Nod-like receptor protein 3 (NLRP3) inflammasome is activated by mitochondrial reactive oxygen species (mROS) during I/R injury via direct interactions between the inflammasome and thioredoxin-interacting protein (TXNIP). Firstly, we found that NLRP3 inflammasome activation was induced by I/R injury, peaking at day 3 after reperfusion. Consistent with this observation, NLRP3 deletion significantly attenuated I/R-induced kidney damage and markers of inflammasome activation. Then, we observed mitochondrial dysfunction, characterized by ultrastructural changes and cytochrome C (Cyt c) redistribution. Mitochondria-targeted antioxidant MitoTEMPO prevented mROS overproduction and the decline in mitochondrial membrane potential (MMP) in vitro. MitoTEMPO treatment also inhibited NLRP3 inflammasome activation and co-localization of NLRP3 and TXNIP after simulated ischemia/reperfusion (SI/R) injury. Finally, we transfected HK-2 cells with TXNIP siRNA to explore the role of TXNIP in mROS-induced NLRP3 inflammasome activation. We found that TXNIP siRNA significantly inhibited NLRP3 inflammasome activation. These results demonstrate that NLRP3 inflammasome is activated through the mROS-TXNIP-NLRP3 pathway and provide a potential therapeutic target in ischemic AKI.