The activity of the epithelial sodium (Na(+)) channel (ENaC) in the aldosterone-sensitive distal nephron (ASDN) needs to be tightly regulated to match urinary Na(+) excretion with dietary Na(+) intake. The ubiquitin-protein ligase Nedd4-2, which in vitro interacts with ENaC subunits and reduces ENaC cell surface abundance and activity by ubiquitylation of the channel, may participate in the control of ENaC. This study confirms in vivo by reverse-transcriptase-PCR that Nedd4-2 is expressed throughout the nephron and is detectable by immunoblotting in kidney extracts. By immunohistochemistry, Nedd4-2 was found to be strongly expressed in the ASDN, with low staining intensity in the late distal convoluted tubule and early connecting tubule (where apical ENaC is high) and gradually increasing detection levels toward the collecting duct (CD; where apical ENaC is low). Compared with high-Na(+) diet (5% Na(+)), 2 wk of low-Na(+) diet (0.01% Na(+)) drastically reduces Nedd4-2 immunostaining and increases apical ENaC abundance in ASDN. Reduced Nedd4-2 immunostaining is not dependent on increased apical Na(+) entry in the CD, because it is similarly observed in mice with intact and with suppressed apical ENaC activity in the CD. Consistent with a role of mineralocorticoid hormones in the long-term regulation of Nedd4-2, 5-d treatment of cultured CD (mpkCCD(cl4)) cells with 1 microM aldosterone leads to reduction of Nedd4-2 protein expression. It is concluded that Nedd4-2 abundance is regulated by Na(+) diet, by a mechanism that likely involves aldosterone. This regulation may contribute to adaptation of apical ENaC activity to altered Na(+) intake.