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Glucocorticoid regulation of genes in the amiloride-sensitive sodium transport pathway by semicircular canal duct epithelium of neonatal rat

¹ Cellular Biophysics Laboratory, Department of Anatomy and Physiology
² Division of Biology, Bioinformatics Center, Kansas State University, Manhattan, Kansas
³ Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York

The lumen of the inner ear has an unusually low concentration of endolymphatic Na⁺, which is important for transduction processes. We have recently shown that glucocorticoid receptors (GR) stimulate absorption of Na⁺ by semicircular canal duct (SCCD) epithelia. In the present study, we sought to determine the presence of genes involved in the control of the amiloride-sensitive Na⁺ transport pathway in rat SCCD epithelia and whether their level of expression was regulated by glucocorticoids using quantitative real-time RT-PCR. Transcripts were present for -, ß-, and -subunits of the epithelial sodium channel (ENaC); the ₁-, ₃-, ß₁-, and ß₃-isoforms of Na⁺-K⁺-ATPase; inwardly rectifying potassium channels [IC₅₀ of short circuit current (I_sc) for Ba²⁺: 210 µM] Kir2.1, Kir2.2, Kir2.3, Kir2.4, Kir3.1, Kir3.3, Kir4.1, Kir4.2, Kir5.1, and Kir7.1; sulfonyl urea receptor 1 (SUR1); GR; mineralocorticoid receptor (MR); 11ß-hydroxysteroid dehydrogenase (11ß-HSD) types 1 and 2; serum- and glucocorticoid-regulated kinase 1 (Sgk1); and neural precursor cell-expressed developmentally downregulated 4-2 (Nedd4-2). On the other hand, transcripts for the ₄-subunit of Na⁺-K⁺-ATPase, Kir1.1, Kir3.2, Kir3.4, Kir6.1, Kir6.2, and SUR2 were found to be absent, and I_sc was not inhibited by glibenclamide. Dexamethasone (100 nM for 24 h) not only upregulated the transcript expression of -ENaC (4-fold), ß₂-subunit (2-fold) and ß₃-subunit (8-fold) of Na⁺-K⁺-ATPase, Kir2.1 (5-fold), Kir2.2 (9-fold), Kir2.4 (3-fold), Kir3.1 ( 3- fold), Kir3.3 (2-fold), Kir4.2 (3-fold ), Kir7.1 (2-fold), Sgk1 (4-fold), and Nedd4-2 (2-fold) but also downregulated GR (3-fold) and 11ß-HSD1 (2-fold). Expression of GR and 11ß-HSD1 was higher than MR and 11ß-HSD2 in the absence of dexamethasone. Dexamethasone altered transcript expression levels (-ENaC and Sgk1) by activation of GR but not MR. Proteins were present for the -, ß-, and -subunits of ENaC and Sgk1, and expression of - and -ENaC was upregulated by dexamethasone. These findings are consistent with the genomic stimulation by glucocorticoids of Na⁺ absorption by SCCD and provide an understanding of the therapeutic action of glucocorticoids in the treatment of Meniere's disease.

inner ear; vestibular labyrinth; dexamethasone

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