Reactive oxygen species promote tubular injury in diabetic nephropathy: The role of the mitochondrial ros-txnip-nlrp3 biological axis

被引：343

作者：

Han, Yachun ^{[1
]}

Xu, Xiaoxuan ^{[2
]}

Tang, Chengyuan ^{[1
]}

Gao, Peng ^{[1
]}

Chen, Xianghui ^{[1
]}

Xiong, Xiaofen ^{[1
]}

Yang, Ming ^{[1
]}

Yang, Shikun ^{[1
]}

Zhu, Xuejing ^{[1
]}

Yuan, Shuguang ^{[1
]}

Liu, Fuyou ^{[1
]}

Xiao, Li ^{[1
]}

Kanwa, Yashpal S. ^{[3
,4
]}

Sun, Lin ^{[1
]}

机构：

[1] Cent S Univ, Xiangya Hosp 2, Dept Nephrol, Changsha 410011, Hunan, Peoples R China

[2] Cent S Univ, Xiangya Hosp, Hlth Management Ctr, Changsha 410011, Hunan, Peoples R China

[3] Northwestern Univ, Dept Pathol, Chicago, IL 60611 USA

[4] Northwestern Univ, Dept Med, Chicago, IL 60611 USA

来源：

REDOX BIOLOGY | 2018年 / 16卷

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

Diabetic nephropathy; Mitochondria; Reactive oxygen species (ROS); TRX/TXNIP; NLRP3; inflammasome; MitoQ; THIOREDOXIN-INTERACTING PROTEIN; NLRP3 INFLAMMASOME ACTIVATION; ENDOTHELIAL DYSFUNCTION; MYOINOSITOL OXYGENASE; OXIDATIVE STRESS; HIGH-GLUCOSE; CELL-DEATH; EXPRESSION; ROS; OVEREXPRESSION;

D O I：

10.1016/j.redox.2018.02.013

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

NLRP3/IL-1 beta activation via thioredoxin (TRX)/thioredoxin-interacting protein (TXNIP) following mitochondria ROS (mtROS) overproduction plays a key role in inflammation. However, the involvement of this process in tubular damage in the kidneys of patients with diabetic nephropathy (DN) is unclear. Here, we demonstrated that mtROS overproduction is accompanied by decreases in TRX expression and TXNIP up-regulation. In addition, we discovered that mtROS overproduction is also associated with increases in NLRP3/IL-1 beta and TGF-beta expression in the kidneys of patients with DN and db/db mice. We reversed these changes in db/db mice by administering a peritoneal injection of MitoQ, an antioxidant targeting mtROS. Similar results were observed in human tubular HK-2 cells subjected to high-glucose (HG) conditions and treated with MitoQ. Treating HK-2 cells with MitoQ suppressed the dissociation of TRX from TXNIP and subsequently blocked the interaction between TXNIP and NLRP3, leading to the inhibition of NLRP3 inflammasome activation and IL-beta maturation. The effects of MitoQ were enhanced by pretreatment with TXNIP siRNA and abolished by pretreatment with monosodium urate (MSU) and TRX siRNA in vitro. These results suggest that mitochondrial ROS-TXNIP/NLRP3/IL-1 beta axis activation is responsible for tubular oxidative injury, which can be ameliorated by MitoQ via the inhibition of mtROS overproduction.

引用

页码：32 / 46

页数：15

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