Nedd4-2 (NEDD4L), a ubiquitin protein ligase of the C2-WW-HECT family (the Nedd4 family), is implicated in the regulation of a number of membrane proteins, including the amiloride-sensitive epithelial sodium channel (ENaC) (1). Previous work from our laboratory has demonstrated an essential role of Nedd4-2 in the lungs where Nedd4-2 deficiency results in increased membrane localization and activity of ENaC leading to premature foetal lung fluid clearance, drying of the lung epithelia, pulmonary distress and perinatal lethality of the knockout mice (2). In addition, we noted that Nedd4-2 deficient mice have a progressive kidney injury phenotype (3). Using a kidney tubule-specific Nedd4-2 knockout mouse we found that the nephropathy was associated with elevated ENaC expression, increased Na+ reabsorption, hypertension and reduced levels of aldosterone. Further characterization indicated significantly increased tubular epithelial cell apoptosis, dilated tubules, fibrosis, kidney injury and immune cell infiltration. Interestingly, the extent of kidney injury was partially blocked by inhibiting ENaC with amiloride, suggesting that ENaC mediated increased Na+ reabsorption is the likely cause of kidney injury phenotype. These results provide direct evidence that Nedd4-2 is a critical regulator of Na+ homeostasis and that increased sodium absorption in the absence of Nedd4-2 results in nephropathy.