The Sodium-Iodide Symporter NIS and Pendrin in Iodide Homeostasis of the Thyroid

Thyroid hormones are essential for normal development and metabolism. Thyroid hormone biosynthesis requires iodide uptake into the thyrocytes and efflux into the follicular lumen, where it is organified on selected tyrosyls of thyroglobulin. Uptake of iodide into the thyrocytes is mediated by an intrinsic membrane glycoprotein, the sodium-iodide symporter (NIS), which actively cotransports two sodium cations per each iodide anion. NIS-mediated transport of iodide is driven by the electrochemical sodium gradient generated by the Na+/K+-ATPase. NIS is expressed in the thyroid, the salivary glands, gastric mucosa, and the lactating mammary gland. TSH and iodide regulate iodide accumulation by modulating NIS activity via transcriptional and posttranscriptional mechanisms. Biallelic mutations in the NIS gene lead to a congenital iodide transport defect, an autosomal recessive condition characterized by hypothyroidism, goiter, low thyroid iodide uptake, and a low saliva/plasma iodide ratio. Pendrin is an anion transporter that is predominantly expressed in the inner ear, the thyroid, and the kidney. Biallelic mutations in the SLC26A4 gene lead to Pendred syndrome, an autosomal recessive disorder characterized by sensorineural deafness, goiter, and impaired iodide organification. In thyroid follicular cells, pendrin is expressed at the apical membrane. Functional in vitro data and the impaired iodide organification observed in patients with Pendred syndrome support a role of pendrin as an apical iodide transporter. This review shows how the sodium-iodide symporter mediates the active transport of iodide at the basolateral membrane of thyrocytes and discusses biallelic mutations in NIS and the effects of pendrin.

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Rapid regulation of thyroid sodium–iodide symporter activity by thyrotrophin and iodine

Journal of Endocrinology ◽

10.1677/joe.1.05643 ◽

2005 ◽

Vol 184 (1) ◽

pp. 69-76 ◽

Cited By ~ 50

Author(s):

Andrea C F Ferreira ◽

Lívia P Lima ◽

Renata L Araújo ◽

Glaucia Müller ◽

Renata P Rocha ◽

...

Keyword(s):

Sodium Iodide ◽

Iodine Content ◽

Concomitant Administration ◽

High Serum ◽

Sodium Iodide Symporter ◽

Physiological Control ◽

Iodide Uptake ◽

Thyroid Hormone Biosynthesis ◽

Serum Tsh

Transport of iodide into thyrocytes, a fundamental step in thyroid hormone biosynthesis, depends on the presence of the sodium–iodide symporter (NIS). The importance of the NIS for diagnosis and treatment of diseases has raised several questions about its physiological control. The goal of this study was to evaluate the influence of thyroid iodine content on NIS regulation by thyrotrophin (TSH) in vivo. We showed that 15-min thyroid radioiodine uptake can be a reliable measurement of NIS activity in vivo. The effect of TSH on the NIS was evaluated in rats treated with 1-methyl-2-mercaptoimidazole (MMI; hypothyroid with high serum TSH concentrations) for 21 days, and after 1 (R1d), 2 (R2d), or 5 (R5d) days of withdrawal of MMI. NIS activity was significantly greater in both MMI and R1d rats. In R2d and R5d groups, thyroid iodide uptake returned to normal values, despite continuing high serum TSH, possibly as a result of the re-establishment of iodine organification after withdrawal of MMI. Excess iodine (0.05% NaI for 6 days) promoted a significant reduction in thyroid radioiodide uptake, an effect that was blocked by concomitant administration of MMI, confirming previous findings that iodine organification is essential for the iodide transport blockade seen during iodine overload. Therefore, our data show that modulation of the thyroid NIS by TSH depends primarily on thyroid iodine content and, further, that the regulation of NIS activity is rapid.

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Association of Low Sodium-Iodide Symporter Messenger Ribonucleic Acid Expression in Malignant Thyroid Nodules with Increased Intracellular Protein Staining

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-0353 ◽

2008 ◽

Vol 93 (10) ◽

pp. 4141-4145 ◽

Cited By ~ 29

Author(s):

Ana Karina M. B. Sodré ◽

Ileana G. S. Rubio ◽

Ana Luiza R. Galrão ◽

Meyer Knobel ◽

Eduardo K. Tomimori ◽

...

Keyword(s):

Sodium Iodide ◽

Thyroid Nodules ◽

Basolateral Membrane ◽

Tsh Receptor ◽

Sodium Iodide Symporter ◽

Rt Pcr ◽

Intracellular Protein ◽

Iodide Uptake ◽

Receptor Proteins ◽

Benign Nodules

Context: The expression of sodium iodide symporter (NIS) is required for iodide uptake in thyroid cells. Benign and malignant thyroid tumors have low iodide uptake. However, previous studies by RT-PCR or immunohistochemistry have shown divergent results of NIS expression in these nodules. Objective: The objective of the study was to investigate NIS mRNA transcript levels, compare with NIS and TSH receptor proteins expression, and localize the NIS protein in thyroid nodules samples and their surrounding nonnodular tissues (controls). Design: NIS mRNA levels, quantified by real-time RT-PCR, and NIS and TSH receptor proteins, evaluated by immunohistochemistry, were examined in surgical specimens of 12 benign and 13 malignant nodules and control samples. Results: When compared with controls, 83.3% of the benign and 100% of the malignant nodules had significantly lower NIS gene expression. Conversely, 66.7% of the benign and 100% of malignant nodules had stronger intracellular NIS immunostaining than controls. Low gene expression associated with strong intracellular immunostaining was most frequently detected in malignant (100%) than benign nodules (50%; P = 0.005). NIS protein was located at the basolateral membrane in 24% of the control samples, 8.3% of the benign, and 15.4% of the malignant nodules. The percentage of benign nodules with strong TSH receptor positivity (41.6%) was higher than malignant (7.7%). Conclusion: We confirmed that reduced NIS mRNA expression in thyroid malignant nodules is associated with strong intracellular protein staining and may be related to the inability of the NIS protein to migrate to the cellular basolateral membrane. These results may explain the low iodide uptake of malignant nodules.

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Identification of novel sodium iodide symporter (NIS) interactors which modulate iodide uptake

Endocrine Abstracts ◽

10.1530/endoabs.44.oc3.4 ◽

2016 ◽

Author(s):

Alice Fletcher ◽

Vikki Poole ◽

Bhavika Modasia ◽

Waraporn Imruetaicharoenchoke ◽

Rebecca Thompson ◽

...

Keyword(s):

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Iodide Uptake

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Identification of novel sodium iodide symporter interactors which modulate iodide uptake

Endocrine Abstracts ◽

10.1530/endoabs.50.oc3.6 ◽

2017 ◽

Author(s):

Alice Fletcher ◽

Vikki Poole ◽

Bhavika Modasia ◽

Waraporn Imruetaicharoenchoke ◽

Rebecca Thompson ◽

...

Keyword(s):

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Iodide Uptake

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The importance of sodium/iodide symporter (NIS) for thyroid cancer management

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302007000500004 ◽

2007 ◽

Vol 51 (5) ◽

pp. 672-682 ◽

Cited By ~ 36

Author(s):

Denise P. Carvalho ◽

Andrea C.F. Ferreira

Keyword(s):

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Therapeutic Tool ◽

Iodide Transport ◽

Cancer Management ◽

Thyroid Hormone Biosynthesis ◽

Nis Gene ◽

Hormone Biosynthesis ◽

Tumoral Cells

The thyroid gland has the ability to uptake and concentrate iodide, which is a fundamental step in thyroid hormone biosynthesis. Radioiodine has been used as a diagnostic and therapeutic tool for several years. However, the studies related to the mechanisms of iodide transport were only possible after the cloning of the gene that encodes the sodium/iodide symporter (NIS). The studies about the regulation of NIS expression and the possibility of gene therapy with the aim of transferring NIS gene to cells that normally do not express the symporter have also become possible. In the majority of hypofunctioning thyroid nodules, both benign and malignant, NIS gene expression is maintained, but NIS protein is retained in the intracellular compartment. The expression of NIS in non-thyroid tumoral cells in vivo has been possible through the transfer of NIS gene under the control of tissue-specific promoters. Apart from its therapeutic use, NIS has also been used for the localization of metastases by scintigraphy or PET-scan with 124I. In conclusion, NIS gene cloning led to an important development in the field of thyroid pathophysiology, and has also been fundamental to extend the use of radioiodine for the management of non-thyroid tumors.

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Effect of Iodide on Human Choriogonadotropin, Sodium-Iodide Symporter Expression, and Iodide Uptake in BeWo Choriocarcinoma Cells

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-2358 ◽

2007 ◽

Vol 92 (10) ◽

pp. 4046-4051 ◽

Cited By ~ 17

Author(s):

Huika Li ◽

Kerry Richard ◽

Brett McKinnon ◽

Robin H. Mortimer

Keyword(s):

Gene Expression ◽

Protein Expression ◽

Mrna Expression ◽

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Iodide Uptake ◽

Hormone Synthesis ◽

Human Choriogonadotropin ◽

Fetal Thyroid ◽

Choriocarcinoma Cells

Abstract Context: Active placental transport of maternal iodide by the thyroidal sodium iodide symporter (NIS) provides an essential substrate for fetal thyroid hormone synthesis. NIS is expressed in trophoblast and is regulated by human choriogonadotropin (hCG). In thyroid, iodide down-regulates expression of several genes including NIS. Placentas of iodine-deficient rats demonstrate up-regulation of NIS mRNA, suggesting a role for iodide in regulating placental NIS. Objectives and Methods: The objectives were to examine effects of iodide on expression of NIS and hCG in BeWo choriocarcinoma cells. Gene expression was studied by quantitative real-time PCR. Effects on NIS protein expression were assessed by Western blotting. Functional activity of NIS was measured by 125I uptake. Expression of hCG protein was assessed by immunoassay of secreted hormone. Results: Iodide inhibited NIS mRNA and membrane protein expression as well as 125I uptake, which were paralleled by decreased βhCG mRNA expression and protein secretion. Iodide had no effects on pendrin expression. Addition of hCG increased NIS mRNA expression. This effect was partially inhibited by addition of iodide. The inhibitory effects of iodide on NIS mRNA expression were abolished by propylthiouracil and dithiothreitol. Conclusions: We conclude that expression of placental NIS is modulated by maternal iodide. This may occur through modulation of hCG effects on NIS and hCG gene expression.

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A nonradioactive iodide uptake assay for sodium iodide symporter function

Analytical Biochemistry ◽

10.1016/j.ab.2009.08.038 ◽

2010 ◽

Vol 396 (1) ◽

pp. 91-95 ◽

Cited By ~ 30

Author(s):

Fanny Waltz ◽

Lucie Pillette ◽

Yves Ambroise

Keyword(s):

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Iodide Uptake ◽

Uptake Assay

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Reestablishment of In Vitro and In Vivo Iodide Uptake by Transfection of the Human Sodium Iodide Symporter (hNIS) in a hNIS Defective Human Thyroid Carcinoma Cell Line

Thyroid ◽

10.1089/thy.2000.10.939 ◽

2000 ◽

Vol 10 (11) ◽

pp. 939-943 ◽

Cited By ~ 36

Author(s):

Jan W.A. Smit ◽

Janny P. Schröder-van der Elst ◽

Marcel Karperien ◽

Ivo Que ◽

Gabri van der Pluijm ◽

...

Keyword(s):

Thyroid Carcinoma ◽

Cell Line ◽

Sodium Iodide ◽

Carcinoma Cell ◽

Human Thyroid ◽

Sodium Iodide Symporter ◽

Iodide Uptake ◽

Thyroid Carcinoma Cell

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Retinol has specific effects on binding of thyrotrophin to cultured porcine thyrocytes

Journal of Endocrinology ◽

10.1677/joe.1.05693 ◽

2004 ◽

Vol 183 (3) ◽

pp. 617-626 ◽

Cited By ~ 4

Author(s):

Eleonore Fröhlich ◽

Anja Witke ◽

Barbara Czarnocka ◽

Richard Wahl

Keyword(s):

Thyroid Cancer ◽

Incubation Time ◽

Time Course ◽

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Iodide Uptake ◽

Specific Effects ◽

Low Concentrations ◽

Apoptotic Effect ◽

Iodine 125

Retinoids are potential candidates for the treatment of thyroid cancer. However, one of the disadvantages of these substances is their dedifferentiating effect on normal non-transformed thyrocytes. To identify conditions under which no dedifferentiating effect of retinol on normal thyrocytes can be observed, we determined iodide uptake, protein iodination, expression of sodium–iodide symporter (NIS) mRNA and protein, and the binding of iodine-125-labelled bTSH in cultured porcine thyrocytes. Combination of TSH and ≤6.5 μM retinol increased iodide uptake and protein iodination compared with TSH alone over the entire incubation time, whereas TSH plus ≥13 μM retinol increased the uptake of iodine-125 only during the first 12 h but decreased it after 30 h and longer. After ≥30 h incubation times with ≥13 μM retinol, the fraction of apoptotic cells was enhanced and proliferation decreased. The incubation with retinol enhanced the binding of [125I]bTSH to thyrocytes, but did not influence expression of the NIS. With low retinol concentrations, the effect on the binding of TSH apparently predominated and retinol increased thyroid function; with higher concentrations the pro-apoptotic effect of retinol overlapped and a two-phased time course resulted. It can be concluded that low concentrations of retinol also exert differentiating effects in normal thyrocytes.

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