The Acute Inhibitory Effect of Iodide Excess on Sodium/Iodide Symporter Expression and Activity Involves the PI3K/Akt Signaling Pathway

Author(s)

Serrano-Nascimento, Caroline ^[1] ; Teixeira, Silvania da Silva ^[1] ; Pablo Nicola, Juan ^[2] ; Nachbar, Renato Tadeu ^[1] ; Maria Masini-Repiso, Ana ^[2] ; Nunes, Maria Tereza ^[1]

Affiliation

^[1] Univ Sao Paulo, Dept Physiol & Biophys, Inst Biomed Sci, BR-05508000 Sao Paulo - Brazil

^[2] Univ Nacl Cordoba, Fac Ciencias Quim, Dept Bioquim Clin, Ctr Invest Bioquim Clin & Inmunol, Consejo Nacl In, RA-5000 Cordoba - Argentina

• Document type: Journal article
• Source: Endocrinology; v. 155, n. 3, p. 1145-1156, MAR 2014.
• Web of Science Citations: 48

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- excesson 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 (Akt 1/2 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 productionin 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. (AU)

• FAPESP's process: 09/17834-6 - Study of the molecular basis of the short-term regulation of the Na+/I- symporter (NIS) and pendrin gene expression in rats thyroid and PCCl3 cells: possible contribution to the comprehension of the Wolff-Chaikoff effect and the escape phenomenon
• Grantee: Maria Tereza Nunes
• Support Opportunities: Regular Research Grants