Expression, transcription, and possible antagonistic interaction of the human Nedd4L gene variant: implications for essential hypertension.
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 NH(2) 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.
Araki
Naomi
N
Department of Medical Science and Cardio-Renal Medicine, Yokohama City University Graduate School of Medicine, Kanagawa-ken, Japan.
Umemura
Masanari
M
Miyagi
Yohei
Y
Yabana
Machiko
M
Miki
Yuko
Y
Tamura
Koichi
K
Uchino
Kazuaki
K
Aoki
Reina
R
Goshima
Yoshio
Y
Umemura
Satoshi
S
Ishigami
Tomoaki
T
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003106:Colon / Q000378:metabolism / Q000473:pathology; D004594:Electrophysiology; D056827:Endosomal Sorting Complexes Required for Transport; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D000075702:Nedd4 Ubiquitin Protein Ligases; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D029867:Xenopus Proteins; D014982:Xenopus laevis
D056827:Endosomal Sorting Complexes Required for Transport; D020033:Protein Isoforms; D012333:RNA, Messenger; D029867:Xenopus Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618485:Nedd4L protein, human; C000618460:nedd4l protein, Xenopus; D044767:Ubiquitin-Protein Ligases