Regulation of Type I 5′ -Deiodinase by Thyroid Hormone and Dexamethasone in Rat Liver and Kidney Cells

Abstract

Type I 5′-deiodinase (5′D-I) is crucial for the generation of circulating 3,5,3′-triiodothyronine (T₃) and so is a major determinant of thyroid hormone action. Liver and kidney 5′D-I activity is reduced in nonthyroidal illness (NTI), but the exact cause of reduced 5′D-I activity remains unknown. Elevated circulating glucocorticoid hormone concentrations are one factor postulated to play a role. We have studied regulation of 5′D-I expression in cultured rat liver (φ₁) and kidney (NRK-52E) cells in response to treatment with T₃ and the glucocorticoid dexamethasone. 5′D-I mRNA was measured by Northern hybridization and 5′D-I activity was measured in a substrate conversion assay. Expression of the sodium pump α1-subunit (Na⁺/K⁺-ATPase α₁-subunit) mRNA was measured as an index of T₃ and dexamethasone effects. In φ₁ liver cells, T₃ increased 5′D-I mRNA by 76 ± 17% and 5′D-I activity by 101 ± 30% (all results mean ± SEM; n = 9). Dexamethasone increased 5′D-I mRNA by 55 ± 16% and 5′D-I activity by 128 ± 6%. In NRK-52E rat kidney cells, 5′D-I mRNA increased by 87 ± 15% with T₃ treatment and by 76 ± 14% with dexamethasone. 5′D-I activity in NRK-52E cells was measurable only after stimulation by combined T₃ and dexamethasone treatment. Na⁺/K⁺-ATPase α1-subunit mRNA expression was stimulated following T₃ and dexamethasone treatment in both cell lines. These results provide evidence for direct pretranslational regulation of 5′D-I by T₃ and dexamethasone in both rat liver and kidney cells. Our findings do not support the hypothesis that glucocorticoids are directly responsible for inhibition of 5′D-I enzyme activity in NTI.