Thyroid Hormone Beta Receptor Mutation Causes Renal Dysfunction and Impairment of ClC-2 Chloride Channel Expression in Mouse Kidney

Background/Aims: Mutations in the thyroid hormone receptor β (TR-β) gene result in resistance to thyroid hormone (RTH). Mutation Δ337T in the TR-β gene has been shown to have the characteristics of RTH syndrome in mice. The aim of this work was to study the possible involvement of TR-β receptor in thyroid modulation of ClC-2 in mouse kidney. Methods: Expression of mouse (Δ337T and normal C57BL/6) renal RNA and protein expression were studied by reverse transcriptase-polymerase chain reaction and Western blot, respectively, in mice with hyper- or hypothyroidism. Renal function was studied by analysis of urinary electrolyte excretion. Studies of the ClC-2 promoter region were performed in immortalized renal proximal tubule (IRPT) cells. Results: In RTH syndrome mice (Δ337T), renal dysfunction was found to be associated with changes in the fractional excretion of sodium (FENa) and chloride (FECl). ClC-2 chloride channel mRNA and protein expression were found to be decreased by 40% in heterozygous and homozygous mutant mouse kidneys and high levels of plasma thyroid hormone were detected in both groups. Hypothyroidism induced by methimazole decreased the renal expression of ClC-2 in normal mice but not in Δ337T mutant mice. In in vitro studies performed on IRPT cells subjected to thyroid hormone treatment, the promoter region of the ClC-2 chloride channel was stimulated in a dose-dependent manner. Conclusions: This work emphasizes the importance of thyroid hormone in electrolyte handling along the nephron and suggests its participation in renal ClC-2 gene transcription via the TR-β receptor pathway.