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

TXNIP公司 生产过剩 线粒体ROS 炎症体 活性氧 硫氧还蛋白相互作用蛋白 化学 硫氧还蛋白 细胞生物学 氧化应激 粒体自噬 线粒体 糖尿病肾病 细胞凋亡 自噬 生物化学 生物 内分泌学 受体
作者
Yachun Han,Xiaoxuan Xu,Chengyuan Tang,Peng Gao,Xianghui Chen,Xiaofen Xiong,Ming Yang,Shikun Yang,Xuejing Zhu,Shuguang Yuan,Fuyou Liu,Li Xiao,Yashpal S. Kanwar,Lin Sun
出处
期刊:Redox biology [Elsevier]
卷期号:16: 32-46 被引量:266
标识
DOI:10.1016/j.redox.2018.02.013
摘要

NLRP3/IL-1β 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-1β and TGF-β 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-1β 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-1β axis activation is responsible for tubular oxidative injury, which can be ameliorated by MitoQ via the inhibition of mtROS overproduction.
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