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Discordant effects of corticosteroids and expression of subunits on ENaC activity

¹Department of Internal Medicine, University of Iowa, and ²Veterans Affairs Medical Center, Iowa City, Iowa

Submitted 14 May 2007 ; accepted in final form 28 June 2007

In renal distal nephron and airway epithelial cells, adrenocortical steroids increase epithelial Na⁺ channel (ENaC) activity and also markedly increase the expression of the -subunit. The present experiments were designed to reconstitute this steroid effect in ENaC-expressing cells by overexpressing the subunits whose expression is enhanced by corticosteroids. In renal collecting duct monolayers, corticosteroids increased ENaC activity 5- to 8-fold, endogenous -ENaC mRNA and protein 10-fold, and -ENaC protein and mRNA 1.2- to 2-fold. -ENaC expression was unchanged. To determine whether this increase in expression was sufficient to increase ENaC activity, we used a regulated adenovirus system to increase expression of each subunit alone and in combination. Unexpectedly, increased expression of the - and/or -subunit had no effect on ENaC activity in collecting duct cells or lung epithelial cells. In contrast, a small increase in -ENaC expression increased ENaC activity about threefold. This increase in activity was additive to the effect of steroids. Thus, even though corticosteroids strongly increase -ENaC expression and moderately increase -ENaC expression, these effects are not, by themselves, sufficient to increase ENaC activity. Knockdown experiments are consistent with the idea that the increased expression of -ENaC is necessary for the full steroid effect on ENaC. Increased expression of -ENaC and corticosteroid treatment enhances ENaC activity by parallel, noninteracting pathways. These results underscore the importance of other actions of steroid hormones for long-term enhancement of ENaC activity and raise new possibilities for regulation of ENaC activity by -ENaC expression.

adenovirus; Na⁺ transport; kidney; lung; aldosterone