title: Sodium fluoride induces nephrotoxicity via oxidative stress-regulated mitochondrial SIRT3 signaling pathway.
abstract: Accumulation of mitochondrial reactive oxygen species (mROS) has been implicated in the pathogenesis of fluorosis. As the main mitochondrial deacetylase, SIRT3 is closely associated with oxidative stress. To investigate the role of SIRT3 in response to sodium fluoride (NaF)-induced nephrotoxicity. Our results showed that NaF treatment impaired mitochondrial ultrastructure, decreased cell viability and increased apoptosis in TCMK-1 cells. Oxidative stress, detected by mROS and 8-Hydroxy-2'-deoxyguanosine (8-OHdG) were higher in NaF-treated cells, accompanied by decreased level of reduced glutathione (GSH). NaF reduces manganese superoxide dismutase (SOD2) expression through SIRT3-mediated DNA-binding activity of FoxO3a and decrease SOD2 activity by inhibiting SIRT3-mediated deacetylation. These effects were ameliorated by overexpression of SIRT3. Peroxisome proliferator-activated receptor-coactivator 1a (PGC-1α) interacted with nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) that bound to SIRT3 promoter to regulate SIRT3 expression. The study provides new insights into a critical NRF2/PGC-1α-SIRT3 pathway in response to NaF-induced nephritic oxidative injury. In vivo treatment of SIRT3-expressing adenovirus protects against NaF-induced nephritic injury in mice. Moreover, mechanistic study revealed that ERK1/2 activation was associated with increased apoptosis induced by NaF. In conclusion, these data shedding light on new approaches for treatment of NaF-induced nephrotoxicity.
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.|Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Song
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.|Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Fu
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.|Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China.
authors.forename: Jingcheng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.|Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China.
authors.forename: Jiamin
authors.initials: J
authors.lastname: Zhao
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.|Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China.
authors.forename: Mengke
authors.initials: M
authors.lastname: Yuan
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.|Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China. zhangy1956@sina.com.|Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China. zhangy1956@sina.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China. hbwu029@nwsuaf.edu.cn.|Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China. hbwu029@nwsuaf.edu.cn.
authors.forename: Haibo
authors.initials: H
authors.lastname: Wu