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 beta (TR-beta) gene result in resistance to thyroid hormone (RTH). Mutation Delta337T in the TR-beta 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-beta receptor in thyroid modulation of ClC-2 in mouse kidney. METHODS Expression of mouse (Delta337T 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 (Delta337T), renal dysfunction was found to be associated with changes in the fractional excretion of sodium (FE(Na)) and chloride (FE(Cl)). 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 Delta337T 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-beta receptor pathway.