Sodium fluoride induces nephrotoxicity via oxidative stress-regulated mitochondrial SIRT3 signaling pathway.
Sodium fluoride induces nephrotoxicity via oxidative stress-regulated mitochondrial SIRT3 signaling pathway.
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DOI：
10.1038/s41598-017-00796-3
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发表时间：
2017-04-06
影响因子：
4.6
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Song C;Fu B;Zhang J;Zhao J;Yuan M;Peng W;Zhang Y;Wu H
线粒体活性氧（mROS）的积累与氟中毒的发病机制有关。SIRT3作为线粒体主要的去乙酰化酶，与氧化应激密切相关。探讨SIRT3在氟化钠（NaF）所致肾毒性反应中的作用。结果表明，NaF处理可使TCMK-1细胞线粒体超微结构受损，细胞活力降低，细胞凋亡增加。mROS检测的氧化应激和8-羟基-2 ' -脱氧鸟苷（8-OHdG）在naff处理的细胞中升高，并伴有还原性谷胱甘肽（GSH）水平降低。NaF通过sirt3介导的FoxO3a dna结合活性降低锰超氧化物歧化酶（SOD2）表达，通过抑制sirt3介导的去乙酰化降低SOD2活性。过表达SIRT3可改善这些影响。过氧化物酶体增殖物激活受体辅助激活因子1a （PGC-1α）与核因子红细胞2 （NF-E2）相关因子2 （NRF2）相互作用，结合SIRT3启动子调节SIRT3的表达。该研究为NRF2/PGC-1α-SIRT3通路在naff诱导的肾病氧化损伤中的应答提供了新的见解。体内处理表达sirt3的腺病毒可保护小鼠免受naff诱导的肾病损伤。此外，机制研究表明，ERK1/2激活与NaF诱导的细胞凋亡增加有关。总之，这些数据揭示了治疗naff引起的肾毒性的新方法。
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.