期刊
REDOX BIOLOGY
卷 16, 期 -, 页码 32-46出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.redox.2018.02.013
关键词
Diabetic nephropathy; Mitochondria; Reactive oxygen species (ROS); TRX/TXNIP; NLRP3 inflammasome; MitoQ
资金
- National Natural Science Foundation of China (NSFC) [81470960]
- NSFC [81730018]
- National Key R&D Program of China [2016YFC1305501]
- Key Research & Development Plan of Hunan Province [2016JC2061]
- NIH [DK60635]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK060635] Funding Source: NIH RePORTER
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.
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