Nedd4-2 is a well-known ubiquitin ligase that regulates the expression of several cell surface proteins. Our previous work showed that mice deficient in Nedd4-2 in kidney (Nedd4-2Ksp1.3) display a progressive kidney disease characterized by the presence of dilated/cystic tubules, fibrosis, apoptosis and elevated levels of kidney injury markers.1 This was associated with elevated expression of the Nedd4-2 substrate epithelial sodium channel (ENaC) and the cystic phenotype could be partially rescued by administration of the ENaC blocker amiloride. We now observe that dietary sodium is crucial in this renal pathology. Specially, a low salt diet fed to nursing pups (through a mother also on low salt diet) till 40 days (p40) can substantially reduce the kidney damage in Nedd4-2Ksp1.3 mice. Conversely, a high salt diet exacerbates the disease with significant damage evident at p20. More recently, we have conducted experiments in adult mice. High sodium diet fed Nedd4-2Ksp1.3 mice displayed loss of body weight, severe polyuria, polydipsia, reduced glomerular filtration rate (GFR), markedly increased levels of kidney injury and fibrosis. This kidney pathology was largely rescued in the low sodium diet fed group. Sodium homeostasis and the associated water balance by kidney is critical for the maintenance of blood volume and blood pressure. Our studies will provide further insight in understanding the role of Nedd4-2 in sodium homeostasis and renal function.