Dietary sodium modulates nephropathy in Nedd4-2-deficient mice.,Cell Death and Differentiation

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Dietary sodium modulates nephropathy in Nedd4-2-deficient mice.
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2019-12-04 , DOI: 10.1038/s41418-019-0468-5
Jantina A Manning ₁ , Sonia S Shah ₁ , Tanya L Henshall ₁ , Andrej Nikolic ₁ , John Finnie _{2,

3} , Sharad Kumar _{1,

2}

Affiliation

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.

中文翻译：

膳食钠调节 Nedd4-2 缺陷小鼠的肾病。

通过严格控制 Na+ 过滤和重吸收来维持盐稳态。在肾单位的远端部分，泛素蛋白连接酶 Nedd4-2 调节膜丰度，从而调节上皮 Na+ 通道 (ENaC) 的活性，这是 Na+ 重吸收的速率限制。小鼠中的 Nedd4-2 缺乏导致 ENaC 升高和肾病，但饮食盐对此的贡献尚未确定。在这项研究中，我们表明高饮食 Na+ 会加剧 Nedd4-2 缺陷小鼠的肾损伤，显着扰乱正常的出生后肾发生并导致肾发育不良的多灶性区域、肾损伤标志物增加和肾功能下降。在对照小鼠中，高膳食 Na+ 导致 ENaC 水平降低。然而，即使在高饮食 Na+ 后，Nedd4-2 缺陷的肾脏仍保持升高的 ENaC，这表明无法有效下调 ENaC 是疾病的盐敏感性的原因。重要的是，低饮食 Na+ 显着改善了 Nedd4-2 缺陷小鼠的肾病。我们的结果表明，由于 ENaC 失调，Nedd4-2 缺陷小鼠的肾损伤对饮食 Na+ 敏感，这可能对肾病患者的疾病管理产生影响。

更新日期：2019-12-04

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