The ubiquitin ligase NEDD4-2/NEDD4L regulates both sodium homeostasis and fibrotic signaling to prevent end-stage renal disease

Kidney disease progression can be affected by Na(+) abundance. A key regulator of Na(+) homeostasis is the ubiquitin ligase NEDD4-2 and its deficiency leads to increased Na(+) transport activity and salt-sensitive progressive kidney damage. However, the mechanisms responsible for high Na(+) induced damage remain poorly understood. Here we show that a high Na(+) diet compromised kidney function in Nedd4-2-deficient mice, indicative of progression toward end-stage renal disease. Injury was characterized by enhanced tubule dilation and extracellular matrix accumulation, together with sustained activation of both Wnt/β-catenin and TGF-β signaling. Nedd4-2 knockout in cortical collecting duct cells also activated these pathways and led to epithelial–mesenchymal transition. Furthermore, low dietary Na(+) rescued kidney disease in Nedd4-2-deficient mice and silenced Wnt/β-catenin and TGF-β signaling. Our study reveals the important role of NEDD4-2-dependent ubiquitination in Na(+) homeostasis and protecting against aberrant Wnt/β-catenin/TGF-β signaling in progressive kidney disease.