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

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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.