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Endocrinology. 2014 Mar;155(3):1145-56. doi: 10.1210/en.2013-1665. Epub 2014 Jan 1.

The acute inhibitory effect of iodide excess on sodium/iodide symporter expression and activity involves the PI3K/Akt signaling pathway.

Author information

1
Department of Physiology and Biophysics (C.S.-N., S.d.S.T., R.T.N., M.T.N.), Institute of Biomedical Sciences, University of São Paulo, 05508-000 São Paulo, Brazil; and Centro de Investigaciones en Bioquímica Clínica e Inmunología-Consejo Nacional de Investigaciones Científicas y Técnicas (J.P.N., A.M.M.-R.), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA Córdoba, Argentina.

Abstract

Iodide (I(-)) is an irreplaceable constituent of thyroid hormones and an important regulator of thyroid function, because high concentrations of I(-) down-regulate sodium/iodide symporter (NIS) expression and function. In thyrocytes, activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) cascade also inhibits NIS expression and function. Because I(-) excess and PI3K/Akt signaling pathway induce similar inhibitory effects on NIS expression, we aimed to study whether the PI3K/Akt cascade mediates the acute and rapid inhibitory effect of I(-) excess on NIS expression/activity. Here, we reported that the treatment of PCCl3 cells with I(-) excess increased Akt phosphorylation under normal or TSH/insulin-starving conditions. I(-) stimulated Akt phosphorylation in a PI3K-dependent manner, because the use of PI3K inhibitors (wortmannin or 2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) abrogated the induction of I(-) effect. Moreover, I(-) inhibitory effect on NIS expression and function were abolished when the cells were previously treated with specific inhibitors of PI3K or Akt (Akt1/2 kinase inhibitor). Importantly, we also found that the effect of I(-) on NIS expression involved the generation of reactive oxygen species (ROS). Using the fluorogenic probes dihydroethidium and mitochondrial superoxide indicator (MitoSOX Red), we observed that I(-) excess increased ROS production in thyrocytes and determined that mitochondria were the source of anion superoxide. Furthermore, the ROS scavengers N-acetyl cysteine and 2-phenyl-1,2-benzisoselenazol-3-(2H)-one blocked the effect of I(-) on Akt phosphorylation. Overall, our data demonstrated the involvement of the PI3K/Akt signaling pathway as a novel mediator of the I(-)-induced thyroid autoregulation, linking the role of thyroid oxidative state to the Wolff-Chaikoff effect.

PMID:
24424051
DOI:
10.1210/en.2013-1665
[Indexed for MEDLINE]
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