The activity of the epithelial 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 reduces ENaC cell surface abundance by ubiquitylation of the channel, is thought to participate in the control of ENaC. In this in vivo study on mouse kidneys, we confirm by RT-PCR and Western blotting that Nedd4-2 is expressed in the kidney. Immunohistochemistry reveals Nedd4-2 abundance 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 towards the collecting duct (where apical ENaC is low). Compared with high Na diet (5% Na), two weeks of low Na diet (0.01% Na), drastically reduces Nedd4-2 immunostaining and increases apical ENaC abundance in ASDN. Consistent with a role of mineralocorticoids in the long-term regulation of Nedd4-2, 5-days treatment of cultured collecting duct cells with aldosterone reduces Nedd4-2 protein abundance. We conclude that Nedd4-2 expression is regulated by Na diet, by a mechanism that likely involves aldosterone. This regulation may contribute to the adaptation of apical ENaC activity to altered Na intake.