Thyroid hormone modulates ClC-2 chloride channel gene expression in rat renal proximal tubules

Abstract

Thyroid hormones has its main role in controlling metabolism, but it can also modulate extracellular fluid volume (ECFV) through its action on the expression and activity of Na + transporters. Otherwise, chloride is the main anion in the ECFV and the influence of thyroid hormones in the regulation of chloride transporters is not yet understood. In this work, we studied the effect of thyroid hormones in the expression of ClC-2, a cell volume-, pH-and voltagesensitive Cl channel, in rat kidney. To analyze the modulation of ClC-2 gene expression by thyroid hormones, we used hypothyroid (Hypo) rats with or without thyroxine (T 4 ) replacement and hyperthyroid (Hyper) rats as our experimental models. Total RNA was isolated and the expression of ClC-2 mRNA was evaluated by a ribonuclease protection assay, and/or semi-quantitative RT-PCR. Renal ClC-2 expression decreased in Hypo rats and increased in Hyper rats. In addition, semiquantitative RT-PCR of different nephron segments showed that these changes were due exclusively to the modulation of ClC-2 mRNA expression by thyroid hormone in convoluted and straight proximal tubules. To investigate whether thyroid hormones action was direct or indirect, renal proximal tubule primary culture cells were prepared and subjected to different T 4 concentrations. ClC-2 mRNA expression was increased by T 4 in a dose-dependent fashion, as analyzed by RT-PCR. Western blotting demonstrated that ClC-2 protein expression followed the same profile of mRNA expression.

Effects of feline hyperthyroidism on kidney function: a review

“…Additionally, GFR upregulation is enhanced secondarily to thyroid hormone-induced increases in expression of messenger RNAs encoding for chloride channels, leading to increased chloride absorption in the proximal tubule and loop of Henle. 20 The decreased intratubular chloride load is sensed in the distal tubule by the macula densa, and via tubuloglomerular feedback, GFR is further upregulated.…”

Research and progress on ClC-2

“…Previous studies have demonstrated that hyperthyroidism and hypothyroidism are associated with chloride (147,148), and the reversal of glomerular filtration by T4 is observed in patients with hypothyroidism (149). In addition, a previous study (89) on T4 suggested that ClC-2 is involved in chloride transport regulated by thyroid hormones in rat renal proximal tubules.…”

“…Previous studies have shown that ClC-2 is also regulated by hormones (89–91), drugs (92–100), proteins (101–107), kinases (108–114), transcription factors (115,116), inhibitors (117–120), scorpion venom (121), α1-adrenoceptor (122), Plasmodium berghei (123), adenosine triphosphate (124,125), ClH 3 (40,126–137), permeant anions (138,139), membrane cholesterol (140) and the tyrosine endocytosis motif (141). …”

Graves’ Disease and the Risk of End-Stage Renal Disease: A Korean Population-Based Study

“…Thyroid hormones directly influence renal tubular function and the cardiovascular system. Thyroid hormones affect the activity of renal tubular ion transporters, and hyperthyroidism stimulates the activity of most transporters, except for aquaporins [ 19 , 20 ]. Moreover, thyroid hormones increase cardiac contractility by regulating the genes responsible for myocardial contraction and electrochemical signaling and decrease vascular smooth muscle tone and reactivity by stimulating nitric oxide synthase activity in the heart, kidney, and aorta [ 21 , 22 ].…”