Deletion of Nedd4-2 results in progressive kidney disease in mice.
Deletion of Nedd4-2 results in progressive kidney disease in mice.
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DOI：
10.1038/cdd.2017.137
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发表时间：
2017-12
影响因子：
12.4
通讯作者：
Kumar S
中科院分区：
文献类型：
--
作者：
Henshall TL;Manning JA;Alfassy OS;Goel P;Boase NA;Kawabe H;Kumar S
NEDD4-2(NEDD4L)是Nedd4家族的一种泛素蛋白连接酶，是细胞表面表达和阿米洛利敏感的上皮钠通道(ENaC)活性的关键调节因子。虽然Nedd4-2的亚型等位基因在小鼠中显示出盐敏感型高血压，但完全敲除会由于ENaC细胞表面水平的增加而导致肺窘迫和围产儿死亡。我们现在发现，Nedd4-2缺乏还会导致意外的进行性肾损伤表型，与ENaC和Na+Cl−共转运体表达升高、Na+重吸收增加、高血压和显著降低的醛固酮水平相关。观察到的肾病的特点是纤维化，肾小管上皮细胞凋亡，肾小管扩张/囊变，肾脏损伤标志物表达增加和免疫细胞浸润，这些特征使人联想到人类慢性肾脏疾病。重要的是，我们证明了通过用阿米洛利阻断ENaC可以部分改善肾单位特异性Nedd4-2缺失的小鼠的肾脏损伤程度。这些结果表明，通过ENaC增加的Na+重吸收导致肾脏损伤，并确立了NEDD4-2在预防Na+诱导的肾病中的新作用。与最近的一些报道相反，我们的数据还表明，ENaC是NEDD4-2的主要体内靶点，Nedd4-2缺失与正常Na+饮食下的高血压有关。这些发现进一步揭示了NEDD4-2在肾脏病理生理学中的重要作用。
NEDD4-2 (NEDD4L), a ubiquitin protein ligase of the Nedd4 family, is a key regulator of cell surface expression and activity of the amiloride-sensitive epithelial Na+ channel (ENaC). While hypomorphic alleles of Nedd4-2 in mice show salt-sensitive hypertension, complete knockout results in pulmonary distress and perinatal lethality due to increased cell surface levels of ENaC. We now show that Nedd4-2 deficiency in mice also results in an unexpected progressive kidney injury phenotype associated with elevated ENaC and Na+Cl− cotransporter expression, increased Na+ reabsorption, hypertension and markedly reduced levels of aldosterone. The observed nephropathy is characterized by fibrosis, tubule epithelial cell apoptosis, dilated/cystic tubules, elevated expression of kidney injury markers and immune cell infiltration, characteristics reminiscent of human chronic kidney disease. Importantly, we demonstrate that the extent of kidney injury can be partially therapeutically ameliorated in mice with nephron-specific deletions of Nedd4-2 by blocking ENaC with amiloride. These results suggest that increased Na+ reabsorption via ENaC causes kidney injury and establish a novel role of NEDD4-2 in preventing Na+-induced nephropathy. Contrary to some recent reports, our data also indicate that ENaC is the primary in vivo target of NEDD4-2 and that Nedd4-2 deletion is associated with hypertension on a normal Na+ diet. These findings provide further insight into the critical function of NEDD4-2 in renal pathophysiology.
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影响因子：
3.7
作者：
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影响因子：
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影响因子：
4.8
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影响因子：
13.6
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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