CALL FOR PAPERS Integrative Aspects of Renal Endocrinology Regulation of epithelial Na channels by adrenal steroids: mineralocorticoid and glucocorticoid effects

Frindt G, Palmer LG. Regulation of epithelial Na channels by adrenal steroids: mineralocorticoid and glucocorticoid effects. Am J Physiol Renal Physiol 302: F20–F26, 2012. First published October 19, 2011; doi:10.1152/ajprenal.00480.2011.—Epithelial Na channels (ENaC) can be regulated by both mineralocorticoid and glucocorticoid hormones. In the mammalian kidney, effects of mineralocorticoids have been extensively studied, but those of glucocorticoids are complicated by metabolism of the hormones and cross-occupancy of mineralocorticoid receptors. Here, we report effects of dexamethasone, a synthetic glucocorticoid, on ENaC in the rat kidney. Infusion of dexamethasone (24 g/day) for 1 wk increased the abundance of ENaC 2.26 0.04-fold. This was not accompanied by an induction of Na currents (INa) measured in isolated split-open collecting ducts. In addition, hormone treatment did not increase the abundance of the cleaved forms of either ENaC or ENaC or the expression of ENaC or ENaC protein at the cell surface. The absence of hypokalemia also indicated the lack of ENaC activation in vivo. Dexamethasone increased the abundance of the Na transporters Na /H exchanger 3 (NHE3; 1.36 0.07-fold), Na -K 2Cl cotransporter 2 (NKCC2; 1.49 0.07-fold), and Na-Cl cotransporter (NCC; 1.72 0.08-fold). Surface expression of NHE3 and NCC also increased with dexamethasone treatment. To examine whether glucocorticoids could either augment or inhibit the effects of mineralocorticoids, we infused dexamethasone (60 g/day) together with aldosterone (12 g/day). Dexamethasone further increased the abundance of ENaC in the presence of aldosterone, suggesting independent effects of the two hormones on this subunit. However, INa was similar in animals treated with dexamethasone aldosterone and with aldosterone alone. We conclude that dexamethasone can occupy glucocorticoid receptors in cortical collecting duct and induce the synthesis of ENaC. However, this induction is not sufficient to produce an increase in functional Na channels in the apical membrane, implying that the abundance of ENaC is not rate limiting for channel formation in the kidney.