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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-1?) 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-1?-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.

SUBMITTER: Song C

PROVIDER: S-EPMC5429606 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Sodium fluoride induces nephrotoxicity via oxidative stress-regulated mitochondrial SIRT3 signaling pathway.

Song Chao C Fu Beibei B Zhang Jingcheng J Zhao Jiamin J Yuan Mengke M Peng Wei W Zhang Yong Y Wu Haibo H

Scientific reports 20170406 1

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'-deoxyg ...[more]

PMID: 28386112

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Project description:BackgroundHigh doses of doxorubicin put cancer patients at risk for developing dilated cardiomyopathy. Previously, we showed that doxorubicin treatment decreases SIRT3 (sirtuin 3), the main mitochondrial deacetylase and increases protein acetylation in rat cardiomyocytes. Here, we hypothesize that SIRT3 expression can attenuate doxorubicin induced dilated cardiomyopathy in vivo by preventing the acetylation of mitochondrial proteins.MethodsNontransgenic, M3-SIRT3 (truncated SIRT3; short isoform), and M1-SIRT3 (full-length SIRT3; mitochondrial localized) transgenic mice were treated with doxorubicin for 4 weeks (8 mg/kg body weight per week). Echocardiography was performed to assess cardiac structure and function and validated by immunohistochemistry and immunofluorescence (n=4-10). Mass spectrometry was performed on cardiac mitochondrial peptides in saline (n=6) and doxorubicin (n=5) treated hearts. Validation was performed in doxorubicin treated primary rat and human induced stem cell derived cardiomyocytes transduced with adenoviruses for M3-SIRT3 and M1-SIRT3 and deacetylase deficient mutants (n=4-10).ResultsEchocardiography revealed that M3-SIRT3 transgenic mice were partially resistant to doxorubicin induced changes to cardiac structure and function whereas M1-SIRT3 expression prevented cardiac remodeling and dysfunction. In doxorubicin hearts, 37 unique acetylation sites on mitochondrial proteins were altered. Pathway analysis revealed these proteins are involved in energy production, fatty acid metabolism, and oxidative stress resistance. Increased M1-SIRT3 expression in primary rat and human cardiomyocytes attenuated doxorubicin-induced superoxide formation, whereas deacetylase deficient mutants were unable to prevent oxidative stress.ConclusionsDoxorubicin reduced SIRT3 expression and markedly affected the cardiac mitochondrial acetylome. Increased M1-SIRT3 expression in vivo prevented doxorubicin-induced cardiac dysfunction, suggesting that SIRT3 could be a potential therapeutic target for mitigating doxorubicin-induced dilated cardiomyopathy.

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Sodium fluoride induces nephrotoxicity via oxidative stress-regulated mitochondrial SIRT3 signaling pathway.

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Sodium fluoride induces nephrotoxicity via oxidative stress-regulated mitochondrial SIRT3 signaling pathway.

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