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Molecular Pathopbysiological Reseatch of ubiquitin ligase,human Nodd4L, for the development ofessentialhyportension

泛素连接酶、人Nodd4L对原发性低血压发生的分子病理学研究

基本信息

批准号：
18590898
负责人：
ISHIGAMI Tomoaki
金额：
$ 2.49万
依托单位：
Yokohama City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

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's syndrome. Among various modulating proteins, E8 ubiquitin ligase, Nedd4L, binds the PY motif of ENaC COOH terminals and catalyzes ubiquitilation of the NH terminal 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, immmohistochemical, 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 evolutionerily new isoform I, is a candidate gene for hypertension.

人体的净钠平衡是通过沿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，位于醛固酮敏感远端肾单位（ASDN）上的上皮钠通道（ENaC）在钠稳态中发挥着关键作用。平衡。对遗传性高血压疾病的分析表明，编码 ENaC 和其他调节蛋白的基因会导致遗传性高血压，例如利德尔综合征，这也支持了这一点。在各种调节蛋白中，E8 泛素连接酶 Nedd4L 结合 ENaC COOH 末端的 PY 基序，并催化蛋白质 NH 末端的泛素化以进行后续降解。人类 Nedd4L 的进化上保守的和进化上新的 C2 结构域是一种隐秘的剪接变体，导致移码突变形成破坏的同工型产物，我们之前报道过。我们重点关注由 SNP (rs4149601) 生成的同工型之一，即同工型 I，并通过分子生物学、免疫组织化学、和电生理学方法。我们发现亚型 I 可能以显性负向方式与其他人类亚型相互作用。这种相互作用可能会异常增加钠的重吸收。综上所述，我们的分析表明人类 Nedd4L 基因，尤其是进化上的新亚型 I，是高血压的候选基因。