Nedd4-2 is a ubiquitin ligase that functions to regulate primarily membrane proteins (predominantly ion channels) by promoting their internalisation and degradation. By controlling the membrane availability of these proteins, Nedd4-2-mediated ubiquitination affects many signalling and physiological outcomes. For example, this enzyme has previously been implicated in diseases of the respiratory, cardiovascular and immune systems. Recently, we have demonstrated that Nedd4-2 also protects against kidney disease1. Specifically, our two mouse models of Nedd4-2 knockout (null and kidney specific) display progressive kidney disease beginning soon after birth. Histological abnormalities in the kidney are characterised by fibrosis, mesenchymal infiltration, apoptosis, cystic tubules and elevated expression of kidney injury markers. We have shown that this is due, at least in part, to higher expression of the Nedd4-2 substrate ENaC (epithelial sodium channel) and can be partially ameliorated by administration of the ENaC blocker amiloride. Recently, we have found that a high sodium diet exacerbates the observed disease and a low sodium diet markedly reduces disease severity and are currently investigating the signalling pathways involved. Together these results suggest that increased sodium reabsorption via ENaC causes kidney injury and establish a novel role of Nedd4-2 in preventing sodium-induced nephropathy.