| First Author | Manning JA | Year | 2020 |
| Journal | Cell Death Differ | Volume | 27 |
| Issue | 6 | Pages | 1832-1843 |
| PubMed ID | 31802037 | Mgi Jnum | J:298023 |
| Mgi Id | MGI:6478177 | Doi | 10.1038/s41418-019-0468-5 |
| Citation | Manning JA, et al. (2020) Dietary sodium modulates nephropathy in Nedd4-2-deficient mice. Cell Death Differ 27(6):1832-1843 |
| abstractText | Salt homeostasis is maintained by tight control of Na(+) filtration and reabsorption. In the distal part of the nephron the ubiquitin protein ligase Nedd4-2 regulates membrane abundance and thus activity of the epithelial Na(+) channel (ENaC), which is rate-limiting for Na(+) reabsorption. Nedd4-2 deficiency in mouse results in elevated ENaC and nephropathy, however the contribution of dietary salt to this has not been characterized. In this study we show that high dietary Na(+) exacerbated kidney injury in Nedd4-2-deficient mice, significantly perturbing normal postnatal nephrogenesis and resulting in multifocal areas of renal dysplasia, increased markers of kidney injury and a decline in renal function. In control mice, high dietary Na(+) resulted in reduced levels of ENaC. However, Nedd4-2-deficient kidneys maintained elevated ENaC even after high dietary Na(+), suggesting that the inability to efficiently downregulate ENaC is responsible for the salt-sensitivity of disease. Importantly, low dietary Na(+) significantly ameliorated nephropathy in Nedd4-2-deficient mice. Our results demonstrate that due to dysregulation of ENaC, kidney injury in Nedd4-2-deficient mice is sensitive to dietary Na(+), which may have implications in the management of disease in patients with kidney disease. |
