Abstract
We investigated the interplay between the mineralocorticoid aldosterone and a mutation mimicking Liddle syndrome in the control of the processing of the epithelia Na(+) channel (ENaC) in mouse kidneys. Rates of processing were assessed by the appearance of the cleaved form of the γENaC subunit. Cleaved γENaC increased with decreasing dietary Na intake and with administration of aldosterone. Measurements taken from isolated tubules indicated that enhanced processing was similar in connecting tubules and in late distal convoluted tubules. In a mouse model with a truncated βENaC subunit (Liddle mice), levels of cleaved γENaC were similar in wild-type (WT) and Liddle animals. The amounts of the full-length form of the subunit were lower in the Liddle mice on control and high-Na diets. Infusion of a low dose of aldosterone produced similar increases in cleaved γENaC in WT and Liddle mice, whereas with maximal doses, levels in Liddle animals were 35% higher than in WT. Acute Na repletion of Na-depleted mice decreased cleaved γENaC with a time constant of 5 h. Rates of decrease were similar in WT and Liddle genotypes. The Liddle's mutation produces modest changes in ENaC processing, and a major effect of the mutation is on the activation of processed channels.NEW & NOTEWORTHY Using a mouse model of Liddle syndrome we show that the effects of the mutation on ENaC activity do not correlate with effects on channel processing. We conclude that the hyperactivity of the channels likely results from increased activity of processed channels residing in the apical membrane.