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/beta -catenin and TGF-beta 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/beta -catenin and TGF-beta signaling. Our study reveals the important role of NEDD4-2-dependent ubiquitination in Na+ homeostasis and protecting against aberrant Wnt/beta -catenin/TGF-beta signaling in progressive kidney disease.

Automated summary

High Na+ diet exacerbates kidney damage in Nedd4-2 deficient mice, indicating progression towards end-stage renal disease with tubule dilation, extracellular matrix accumulation, and activation of multiple signaling pathways. Low Na+ diet rescues kidney disease in Nedd4-2 deficient mice by suppressing aberrant signaling pathways.