title: An isoform of Nedd4-2 is critically involved in the renal adaptation to high salt intake in mice.
abstract: Epithelial sodium channels (ENaCs) play critical roles in the maintenance of fluid and electrolyte homeostasis, and their genetic abnormalities cause one type of hereditary salt-sensitive hypertension, Liddle syndrome. As we reported previously, both human and rodent Nedd4L/Nedd4-2 showed molecular diversity, with and without a C2 domain in their N-terminal. Nedd4L/Nedd4-2 isoforms with a C2 domain are hypothesized to be related closely to ubiquitination of ENaCs. We generated Nedd4-2 C2 domain knockout mice. We demonstrate here that loss of Nedd4-2 C2 isoform causes salt-sensitive hypertension under conditions of a high dietary salt intake in vivo. The knockout mice had reduced urinary sodium excretion, osmotic pressure and increased water intake and urine volume with marked dilatation of cortical tubules while receiving a high salt diet. To the contrary, there was no difference in metabolic data between wild-type and knockout mice receiving a normal control diet. In the absence of Nedd4-2 C2 domain, a high salt intake accelerated ENaC expression. Coimmunoprecipitation studies revealed suppressed ubiquitination for ENaC with a high salt intake. Taken together, our findings demonstrate that during a high oral salt intake the Nedd4-2 C2 protein plays a pivotal role in maintaining adaptive salt handling in the kidney.
authors.affiliation: Yokohama City University Graduate School of Medicine, Department of Medical Science and Cardio-Renal Medicine.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Minegishi
authors.affiliation: Yokohama City University Graduate School of Medicine, Department of Medical Science and Cardio-Renal Medicine.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ishigami
authors.affiliation: Yokohama City University Graduate School of Medicine, Department of Medical Science and Cardio-Renal Medicine.
authors.forename: Tabito
authors.initials: T
authors.lastname: Kino
authors.affiliation: Yokohama City University Graduate School of Medicine, Department of Medical Science and Cardio-Renal Medicine.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Yokohama City University Graduate School of Medicine, Department of Medical Science and Cardio-Renal Medicine.
authors.forename: Rie
authors.initials: R
authors.lastname: Nakashima-Sasaki
authors.affiliation: Yokohama City University Graduate School of Medicine, Department of Medical Science and Cardio-Renal Medicine.
authors.forename: Naomi
authors.initials: N
authors.lastname: Araki
authors.affiliation: Yokohama City University Graduate School of Medicine, Department of Medical Science and Cardio-Renal Medicine.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yatsu
authors.affiliation: Yokohama City University Graduate School of Medicine, Department of Medical Science and Cardio-Renal Medicine.
authors.forename: Megumi
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Yokohama City University Graduate School of Medicine, Department of Medical Science and Cardio-Renal Medicine.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Umemura
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D053503:Epithelial Sodium Channels / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000075702:Nedd4 Ubiquitin Protein Ligases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*; D054875:Ubiquitination
chemical_list: D053503:Epithelial Sodium Channels; D020033:Protein Isoforms; D017673:Sodium Chloride, Dietary; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse