Expression, transcription, and possible antagonistic interaction of the human Nedd4L gene variant -: Implications for essential hypertension
Expression, transcription, and possible antagonistic interaction of the human Nedd4L gene variant -: Implications for essential hypertension
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DOI：
10.1161/hypertensionaha.107.102061
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发表时间：
2008-03-01
期刊：
影响因子：
8.3
通讯作者：
Ishigami, Tomoaki
中科院分区：
文献类型：
--
作者：
Araki, Naomi;Umemura, Masanari;Ishigami, Tomoaki
人体的净钠平衡是通过沿着整个肾单位表达的各种离子转运蛋白来维持的。在这些离子转运蛋白中，沿着醛固酮敏感性远端肾单位（ASDN）的上皮钠通道（ENaC）在钠平衡的稳态中发挥着关键作用。这一点得到了遗传性高血压疾病分析的支持，显示编码ENaC和其他调节蛋白的基因引起遗传性高血压，如Liddle综合征。在各种调节蛋白中，E3泛素连接酶Nedd4L结合ENaC COOH末端的PY基序并催化蛋白质的NH 2末端的泛素化以用于随后的降解。人类Nedd4L是一种隐蔽的剪接变异体，通过移码突变形成破坏的同种型产物，其C2结构域既有进化上保守的，也有进化上新的。我们专注于一个异构体，异构体I，产生的SNP（rs4149601），并研究其表达和与其他异构体的相互作用，通过分子生物学，免疫组织化学和电生理方法。我们发现，亚型I可能与其他人类亚型在显性负性的方式。这种相互作用可能会异常增加钠的重吸收。总之，我们的分析表明，人类Nedd4L基因，特别是进化上新的亚型I，是高血压的候选基因。
Net sodium balances in humans are maintained through various ion transporters expressed along the entire nephron. Among these ion transporters, epithelial sodium channels (ENaC) located along the aldosterone-sensitive distal nephron (ASDN) play a pivotal role in the homeostasis of sodium balance. This is supported by analyses of inherited hypertensive disorders, showing that genes encoding ENaC and other modulatory proteins cause hereditary hypertension, such as Liddle syndrome. Among various modulating proteins, E3 ubiquitin ligase, Nedd4L, binds the PY motif of ENaC COOH terminals and catalyzes ubiquitination of the NH2 terminus of the protein for subsequent degradation. Both evolutionarily conserved and evolutionarily new C2 domains of human Nedd4L, a cryptic splice variant resulting in a disrupted isoform product formed by a frame-shift mutation, were reported previously. We focused on one of the isoforms, isoform I, generated by SNP (rs4149601), and studied its expression and interactions with other isoforms by molecular biological, immunohistochemical, and electrophysiological methods. We found that isoform I may interact with other human isoforms in a dominant-negative fashion. Such interactions might abnormally increase sodium reabsorption. Taken together, our analyses suggest that the human Nedd4L gene, especially the evolutionarily new isoform I, is a candidate gene for hypertension.