Abstract
The sodium/iodide symporter (NIS) mediates active iodide (I−) accumulation in the thyroid, the first step in thyroid hormone (TH) biosynthesis. Mutations in the SLC5A5 gene encoding NIS that result in a non-functional protein lead to congenital hypothyroidism due to I− transport defect (ITD). ITD is a rare autosomal disorder that, if not treated promptly in infancy, can cause mental retardation, as the TH decrease results in improper development of the nervous system. However, in some patients, hypothyroidism has been ameliorated by unusually large amounts of dietary I−. Here we report the first NIS knockout (KO) mouse model, obtained by targeting exons 6 and 7 of the Slc5a5 gene. In NIS KO mice, in the thyroid, stomach, and salivary gland, NIS is absent, and hence there is no active accumulation of the NIS substrate pertechnetate (99mTcO4−). NIS KO mice showed undetectable serum T4 and very low serum T3 levels when fed a diet supplying the minimum I− requirement for rodents. These hypothyroid mice displayed oxidative stress in the thyroid, but not in the brown adipose tissue or liver. Feeding the mice a high-I− diet partially rescued TH biosynthesis, demonstrating that, at high I− concentrations, I− enters the thyroid through routes other than NIS.
Highlights
Na+/I− symporter (NIS) KO mice, in the thyroid, stomach, and salivary gland, NIS is absent, and there is no active accumulation of the NIS substrate pertechnetate (99mTcO4−)
To determine whether NIS was deleted in our NIS KO mouse model, we investigated NIS expression in NIS KO and WT mice by immunohistochemistry (IHC) and western blot (WB) in the thyroid, salivary glands, and stomach
As NIS is expressed in the lactating breast[14], where it mediates the transport of I− to the milk, our hypothesis was that breastfeeding the oldest and second-oldest children supplied them with a high-I− diet, enabling them to produce higher levels of thyroid hormone (TH) than the youngest child and thereby lessening their cognitive deficit
Summary
NIS KO mice, in the thyroid, stomach, and salivary gland, NIS is absent, and there is no active accumulation of the NIS substrate pertechnetate (99mTcO4−). NIS KO mice showed undetectable serum T4 and very low serum T3 levels when fed a diet supplying the minimum I− requirement for rodents These hypothyroid mice displayed oxidative stress in the thyroid, but not in the brown adipose tissue or liver. The Na+/monocarboxylate transporter (SMCT) (Slc5a8) is expressed at the apical membrane of thyroid follicular cells[17]. There are reports of a few ITD patients whose I− intake was unusually high (~100 times higher than the 150 μg/day recommended by the World Health Organization) and whose hypothyroidism was less severe[23, 24] This suggests that, in the absence of a functional NIS, high dietary I− supply may result in some entry of I− into the follicular cells through non-NIS paths, leading to at least modest TH biosynthesis
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