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

Am J Physiol Lung Cell Mol Physiol. 2003 Sep;285(3):L762-72. doi: 10.1152/ajplung.00376.2002. Epub 2003 May 9.


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 alpha1- or beta1-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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brefeldin A / pharmacology
  • Cell Line
  • Cell Membrane / enzymology
  • Dactinomycin / pharmacology
  • Enzyme Activation / drug effects
  • Epithelial Cells / cytology
  • Epithelial Cells / enzymology*
  • Gene Expression Regulation, Enzymologic / drug effects
  • Protein Synthesis Inhibitors / pharmacology
  • Pulmonary Alveoli / cytology
  • Pulmonary Alveoli / enzymology
  • Rats
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / enzymology*
  • Sodium-Potassium-Exchanging ATPase / genetics
  • Sodium-Potassium-Exchanging ATPase / metabolism*
  • Triiodothyronine / pharmacology*


  • Protein Synthesis Inhibitors
  • Triiodothyronine
  • Dactinomycin
  • Brefeldin A
  • Sodium-Potassium-Exchanging ATPase