Glucocorticoid receptor is indispensable for mineralocorticoid receptor‐dependent induction of colonic epithelial Na+ channels

Abstract

Introduction In the colon, electrogenic sodium absorption is controlled by the epithelial Na+ channel (ENaC). We characterized the interplay of glucocorticoids and mineralocorticoids in ENaC signaling which is only poorly understood due to the lack of epithelial cell lines co-expressing functional glucocorticoid (GR) and mineralocorticoid receptors (MR). Methods Interplay of the two receptors was studied in the highly differentiated, human colon cell line HT-29/B6-GR/MR equipped with the complete receptor repertoire of both GR and MR due to stable transfection. Results In contrast to HT-29/B6 cells solely expressing the MR, HT-29/B6-GR/MR cells displayed a physiological response to aldosterone regarding ENaC induction after a pre-incubation step with the GR agonist dexamethasone. Resulting from cooperative effects between the activated GR and the MR, MR protein levels were elevated and MR-dependent transcription of ENaC subunits β and γ was increased. As an additional mechanism involved, transcription of SGK-1 (serum- and glucocorticoid-induced kinase 1) and GILZ (glucocorticoid-induced leucin zipper) - both essential for the rise in apical ENaC levels - were also augmented by the activated MR. Conclusion After generating a new GR/MR colonic cell model we showed that GR expression and GR pre-stimulation were indispensable for the MR-dependent induction of ENaC.