Cargando…
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...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046789/ https://www.ncbi.nlm.nih.gov/pubmed/33854040 http://dx.doi.org/10.1038/s41419-021-03688-7 |
Sumario: | 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. |
---|