Nedd4-2 and the regulation of epithelial sodium transport

Abstract

Nedd4-2 is a ubiquitin ligase previously demonstrated to regulate endocytosis and lyso-somal degradation of the epithelial Na+ channel (ENaC) and other ion channels and trans-porters. Recent studies using Nedd4-2 knockout mice specifically in kidney or lung epithelia has revealed a critical role for this E3 ubiquitin ligase in regulating salt and fluid transport in these tissues/organs and in maintaining homeostasis of body blood pressure. Interest-ingly, the primary targets for Nedd4-2 may differ in these two organs: in the lung Nedd4-2 targets ENaC, and loss of Nedd4-2 leads to excessive ENaC function and to cystic fibro-sis - like lung disease, whereas in the kidney, Nedd4-2 targets the Na+/CI~ cotransporter (NCC) in addition to targeting ENaC. In accord, loss of Nedd4-2 in the distal nephron leads to increased NCC abundanceand function. The aldosterone-responsive kinase, Sgk1, appears to be involved in the regulation of NCC by Nedd4-2 in the kidney, similar to its regulation of ENaC. Collectively, these new findings underscore the physiological importance of Nedd4-2 in regulating epithelial salt and fluid transport and balance. © 2012 Rotin and Staub.