Glucocorticoids stimulate cation absorption by semicircular canal duct epithelium via epithelial sodium channel

Abstract

The semicircular canal duct (SCCD) epithelium is a vestibular epithelial domain that was recently shown to actively contribute to endolymph homeostasis by Cl− secretion under control of β2-adrenergic stimulation. By analogy to other Cl− secretory epithelia, we hypothesized that SCCD also provides an active absorptive pathway for Na+ under corticosteroid control. Measurements of short-circuit current ( Isc) demonstrated stimulation (7–24 h) by the glucocorticoids hydrocortisone (EC50 13 nM), corticosterone (33 nM), prednisolone (70 nM), and dexamethasone (13 nM) over physiologically and therapeutically relevant concentrations and its block by amiloride (IC50 470 nM) and benzamil (57 nM), inhibitors of the epithelial sodium channel (ENaC). Isc was also partially inhibited by basolateral ouabain and Ba2+, indicating the participation of Na+-K+-ATPase and a K+ channel in Na+ transport. By contrast, aldosterone stimulated Isc only at unphysiologically high concentrations (EC50 102 nM). The action of all steroids was blocked by mifepristone (RU-486; Kd ∼0.3 nM) but not by spironolactone ( Kd ∼0.7 μM). Expression of mRNA for the α-, β-, and γ-subunits of ENaC was demonstrated in the presence and absence of glucocorticoids. These findings are the first to identify SCCD in the vestibular labyrinth as a site of physiologically significant ENaC-mediated Na+ absorption and osmotically coupled water flux. They further demonstrate regulation of Na+ transport by natural and therapeutic glucocorticoids. The results provide for the first time an understanding of the therapeutic benefit of glucocorticoids in the treatment of Meniere's disease, a condition that is associated with increased luminal fluid volume.