Sodium Fluoride Arrests Renal G2/M Phase Cell-Cycle Progression by Activating ATM-Chk2-P53/Cdc25C Signaling Pathway in Mice

Cell Physiol Biochem. 2018;51(5):2421-2433. doi: 10.1159/000495899. Epub 2018 Dec 11.


Background/aims: Excessive fluoride intake can induce cytotoxicity, DNA damage and cell-cycle changes in many tissues and organs, including the kidney. However, the underlying molecular mechanisms of fluoride-induced renal cell-cycle changes are not well understood at present. In this study, we used a mouse model to investigate how sodium fluoride (NaF) induces cell-cycle changes in renal cells.

Methods: Two hundred forty ICR mice were randomly assigned to four equal groups for intragastric administration of NaF (0, 12, 24 and 48 mg/kg body weight/day) for 42 days. Kidneys were taken to measure changes of the cell-cycle at 21 and 42 days of the experiment, using flow cytometry, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot methods.

Results: NaF, at more than 12 mg/kg body weight, induced G2/M phase cell-cycle arrest in the renal cells, which was supported by the finding of significantly increased percentages of renal cells in the G2/M phase. We found also that G2/M phase cell-cycle arrest was accompanied by up-regulation of p-ATM, p-Chk2, p-p53, p-Cdc25C, p-CDK1, p21, and Gadd45a protein expression levels; up-regulation of ATM, Chk2, p53, p21, and Gadd45a mRNA expression levels; down-regulation of CyclinB1, mdm2, PCNA protein expression levels; and down-regulation of CyclinB1, CDK1, Cdc25C, mdm2, and PCNA mRNA expression levels.

Conclusion: In this mouse model, NaF, at more than 12 mg/ kg, induced G2/M phase cell-cycle arrest by activating the ATM-Chk2-p53/Cdc25C signaling pathway, which inhibits the proliferation of renal cells and development of the kidney. Activation of the ATM-Chk2-p53/Cdc25C signaling pathway is the mechanism of NaF-induced renal G2/M phase cell-cycle arrest in this model.

Keywords: ATM-Chk2-p53/Cdc25C signaling pathway; G2/M phase arrest; Kidney; Mice; Proliferation; Sodium fluoride.

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Checkpoint Kinase 2 / metabolism
  • Female
  • G2 Phase Cell Cycle Checkpoints / drug effects*
  • Kidney / cytology
  • Kidney / drug effects*
  • Kidney / metabolism
  • Kidney / pathology
  • M Phase Cell Cycle Checkpoints / drug effects*
  • Mice
  • Mice, Inbred ICR
  • Signal Transduction / drug effects*
  • Sodium Fluoride / adverse effects*
  • Tumor Suppressor Protein p53 / metabolism
  • cdc25 Phosphatases / metabolism


  • Tumor Suppressor Protein p53
  • Sodium Fluoride
  • Checkpoint Kinase 2
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Chek2 protein, mouse
  • Cdc25c protein, mouse
  • cdc25 Phosphatases