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Thyroid hormone stimulates Na-K-ATPase activity and its plasma membrane insertion in rat alveolar epithelial cells

Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455

Submitted 4 November 2002 ; accepted in final form 4 April 2003

Na-K-ATPase protein is critical for maintaining cellular ion gradients and volume and for transepithelial ion transport in kidney and lung. Thyroid hormone, 3,3',5-triiodo-L-thyronine (T₃), given for 2 days to adult rats, increases alveolar fluid resorption by 65%, but the mechanism is undefined. We tested the hypothesis that T₃ stimulates Na-K-ATPase in adult rat alveolar epithelial cells (AEC), including primary rat alveolar type II (ATII) cells, and determined mechanisms of the T₃ effect on the Na-KATPase enzyme using two adult rat AEC cell lines (MP48 and RLE-6TN). T₃ at 10^-8 and 10^-5 M increased significantly hydrolytic activity of Na-K-ATPase in primary ATII cells and both AEC cell lines. The increased activity was dose dependent in the cell lines (10^-9-10^-4 M) and was detected within 30 min and peaked at 6 h. Maximal increases in Na-K-ATPase activity were twofold in MP48 and RLE-6TN cells at pharmacological T₃ of 10^-5 and 10^-4 M, respectively, but increases were statistically significant at physiological T₃ as low as 10^-9 M. This effect was T₃ specific, because reverse T₃ (3,3',5'-triiodo-L-thyronine) at 10^-9-10^-4 M had no effect. The T₃-induced increase in Na-K-ATPase hydrolytic activity was not blocked by actinomycin D. No significant change in mRNA and total cell protein levels of Na-K-ATPase were detected with 10^-9-10^-5 M T₃ at 6 h. However, T₃ increased cell surface expression of Na-K-ATPase ₁- or ₁-subunit proteins by 1.7- and 2-fold, respectively, and increases in Na-K-ATPase activity and cell surface expression were abolished by brefeldin A. These data indicate that T₃ specifically stimulates Na-K-ATPase activity in adult rat AEC. The upregulation involves translocation of Na-K-ATPase to plasma membrane, not increased gene transcription. These results suggest a novel nontranscriptional mechanism for regulation of Na-K-ATPase by thyroid hormone.

alveolar cell lines; protein translocation; sodium pump

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