Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension
Identifieur interne : 004509 ( Main/Exploration ); précédent : 004508; suivant : 004510Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension
Auteurs : Caroline Ronzaud [Suisse] ; Dominique Loffing-Cueni [Suisse] ; Pierrette Hausel [Suisse] ; Anne Debonneville [Suisse] ; Sumedha Ram Malsure [Suisse] ; Nicole Fowler-Jaeger [Suisse] ; Natasha A. Boase [Australie] ; Romain Perrier [Suisse] ; Marc Maillard [Suisse] ; Baoli Yang [États-Unis] ; John B. Stokes [États-Unis] ; Robert Koesters [France] ; Sharad Kumar [Australie] ; Edith Hummler [Suisse] ; Johannes Loffing [Suisse] ; Olivier Staub [Suisse]Source :
- The Journal of Clinical Investigation [ 0021-9738 ] ; 2013.
Abstract
The E3 ubiquitin ligase NEDD4-2 (encoded by the
Url:
DOI: 10.1172/JCI61110
PubMed: 23348737
PubMed Central: 3561795
Affiliations:
- Australie, France, Suisse, États-Unis
- Canton de Vaud, Canton de Zurich, Iowa, Île-de-France
- Iowa City, Lausanne, Paris, Zurich
- Université de Zurich, Université de l'Iowa
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Le document en format XML
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<front><div type="abstract" xml:lang="en"><p>The E3 ubiquitin ligase NEDD4-2 (encoded by the <italic>Nedd4L</italic>
gene) regulates the amiloride-sensitive epithelial Na<sup>+</sup>
channel (ENaC/SCNN1) to mediate Na<sup>+</sup>
homeostasis. Mutations in the human β/γENaC subunits that block NEDD4-2 binding or constitutive ablation of exons 6–8 of <italic>Nedd4L</italic>
in mice both result in salt-sensitive hypertension and elevated ENaC activity (Liddle syndrome). To determine the role of renal tubular NEDD4-2 in adult mice, we generated tetracycline-inducible, nephron-specific <italic>Nedd4L</italic>
KO mice. Under standard and high-Na<sup>+</sup>
diets, conditional KO mice displayed decreased plasma aldosterone but normal Na<sup>+</sup>
/K<sup>+</sup>
balance. Under a high-Na<sup>+</sup>
diet, KO mice exhibited hypercalciuria and increased blood pressure, which were reversed by thiazide treatment. Protein expression of βENaC, γENaC, the renal outer medullary K<sup>+</sup>
channel (ROMK), and total and phosphorylated thiazide-sensitive Na<sup>+</sup>
Cl<sup>–</sup>
cotransporter (NCC) levels were increased in KO kidneys. Unexpectedly, <italic>Scnn1a</italic>
mRNA, which encodes the αENaC subunit, was reduced and proteolytic cleavage of αENaC decreased. Taken together, these results demonstrate that loss of NEDD4-2 in adult renal tubules causes a new form of mild, salt-sensitive hypertension without hyperkalemia that is characterized by upregulation of NCC, elevation of β/γENaC, but not αENaC, and a normal Na<sup>+</sup>
/K<sup>+</sup>
balance maintained by downregulation of ENaC activity and upregulation of ROMK.
</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>Australie</li>
<li>France</li>
<li>Suisse</li>
<li>États-Unis</li>
</country>
<region><li>Canton de Vaud</li>
<li>Canton de Zurich</li>
<li>Iowa</li>
<li>Île-de-France</li>
</region>
<settlement><li>Iowa City</li>
<li>Lausanne</li>
<li>Paris</li>
<li>Zurich</li>
</settlement>
<orgName><li>Université de Zurich</li>
<li>Université de l'Iowa</li>
</orgName>
</list>
<tree><country name="Suisse"><region name="Canton de Vaud"><name sortKey="Ronzaud, Caroline" sort="Ronzaud, Caroline" uniqKey="Ronzaud C" first="Caroline" last="Ronzaud">Caroline Ronzaud</name>
</region>
<name sortKey="Debonneville, Anne" sort="Debonneville, Anne" uniqKey="Debonneville A" first="Anne" last="Debonneville">Anne Debonneville</name>
<name sortKey="Fowler Jaeger, Nicole" sort="Fowler Jaeger, Nicole" uniqKey="Fowler Jaeger N" first="Nicole" last="Fowler-Jaeger">Nicole Fowler-Jaeger</name>
<name sortKey="Hausel, Pierrette" sort="Hausel, Pierrette" uniqKey="Hausel P" first="Pierrette" last="Hausel">Pierrette Hausel</name>
<name sortKey="Hummler, Edith" sort="Hummler, Edith" uniqKey="Hummler E" first="Edith" last="Hummler">Edith Hummler</name>
<name sortKey="Loffing Cueni, Dominique" sort="Loffing Cueni, Dominique" uniqKey="Loffing Cueni D" first="Dominique" last="Loffing-Cueni">Dominique Loffing-Cueni</name>
<name sortKey="Loffing, Johannes" sort="Loffing, Johannes" uniqKey="Loffing J" first="Johannes" last="Loffing">Johannes Loffing</name>
<name sortKey="Maillard, Marc" sort="Maillard, Marc" uniqKey="Maillard M" first="Marc" last="Maillard">Marc Maillard</name>
<name sortKey="Malsure, Sumedha Ram" sort="Malsure, Sumedha Ram" uniqKey="Malsure S" first="Sumedha Ram" last="Malsure">Sumedha Ram Malsure</name>
<name sortKey="Perrier, Romain" sort="Perrier, Romain" uniqKey="Perrier R" first="Romain" last="Perrier">Romain Perrier</name>
<name sortKey="Staub, Olivier" sort="Staub, Olivier" uniqKey="Staub O" first="Olivier" last="Staub">Olivier Staub</name>
</country>
<country name="Australie"><noRegion><name sortKey="Boase, Natasha A" sort="Boase, Natasha A" uniqKey="Boase N" first="Natasha A." last="Boase">Natasha A. Boase</name>
</noRegion>
<name sortKey="Kumar, Sharad" sort="Kumar, Sharad" uniqKey="Kumar S" first="Sharad" last="Kumar">Sharad Kumar</name>
</country>
<country name="États-Unis"><region name="Iowa"><name sortKey="Yang, Baoli" sort="Yang, Baoli" uniqKey="Yang B" first="Baoli" last="Yang">Baoli Yang</name>
</region>
<name sortKey="Stokes, John B" sort="Stokes, John B" uniqKey="Stokes J" first="John B." last="Stokes">John B. Stokes</name>
</country>
<country name="France"><region name="Île-de-France"><name sortKey="Koesters, Robert" sort="Koesters, Robert" uniqKey="Koesters R" first="Robert" last="Koesters">Robert Koesters</name>
</region>
</country>
</tree>
</affiliations>
</record>
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