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(Hypertension. 2008;51:773.)
© 2008 American Heart Association, Inc.

Original Articles

Expression, Transcription, and Possible Antagonistic Interaction of the Human Nedd4L Gene Variant

Implications for Essential Hypertension

Naomi Araki; Masanari Umemura; Yohei Miyagi; Machiko Yabana; Yuko Miki; Koichi Tamura; Kazuaki Uchino; Reina Aoki; Yoshio Goshima; Satoshi Umemura; Tomoaki Ishigami

From the Department of Medical Science and Cardio-Renal Medicine (N.A., M.U., Y.Miyagi, M.Y., Y.Miki, K.T., K.U., S.U., T.I.) and the Department of Molecular Pharmacology and Neurobiology (R.A., Y.G.), Yokohama City University Graduate School of Medicine, Kanagawa-ken, Japan.

Correspondence to Tomoaki Ishigami, MD, PhD, Associate Professor, Yokohama City University Graduate School of Medicine, Department of Medical Science and Cardio-Renal Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama-city, Kanagawa-ken, Japan. E-mail tommmish{at}hotmail.com

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.

Key Words: tubular transport • epithelial sodium channel • Nedd4L • essential hypertension