AustralieFrV1, Ncbi, Curation, bibRecord, 001111

Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension

Identifieur interne : 001111 ( Ncbi/Curation ); précédent : 001110; suivant : 001112

Renal 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.

RBID : PMC:3561795

Abstract

The E3 ubiquitin ligase NEDD4-2 (encoded by the Nedd4L gene) regulates the amiloride-sensitive epithelial Na⁺ channel (ENaC/SCNN1) to mediate Na⁺ homeostasis. Mutations in the human β/γENaC subunits that block NEDD4-2 binding or constitutive ablation of exons 6–8 of Nedd4L 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 Nedd4L KO mice. Under standard and high-Na⁺ diets, conditional KO mice displayed decreased plasma aldosterone but normal Na⁺/K⁺ balance. Under a high-Na⁺ 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⁺ channel (ROMK), and total and phosphorylated thiazide-sensitive Na⁺Cl^– cotransporter (NCC) levels were increased in KO kidneys. Unexpectedly, Scnn1a 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⁺/K⁺ balance maintained by downregulation of ENaC activity and upregulation of ROMK.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561795

DOI: 10.1172/JCI61110
PubMed: 23348737
PubMed Central: 3561795

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PMC:3561795

Le document en format XML

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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension</title>
<author><name sortKey="Ronzaud, Caroline" sort="Ronzaud, Caroline" uniqKey="Ronzaud C" first="Caroline" last="Ronzaud">Caroline Ronzaud</name>
<affiliation wicri:level="3"><nlm:aff id="JCI61110">Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Suisse</country>
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<author><name sortKey="Loffing Cueni, Dominique" sort="Loffing Cueni, Dominique" uniqKey="Loffing Cueni D" first="Dominique" last="Loffing-Cueni">Dominique Loffing-Cueni</name>
<affiliation wicri:level="4"><nlm:aff id="JCI61110">Institute of Anatomy, University of Zurich, Zurich, Switzerland.</nlm:aff>
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<author><name sortKey="Hausel, Pierrette" sort="Hausel, Pierrette" uniqKey="Hausel P" first="Pierrette" last="Hausel">Pierrette Hausel</name>
<affiliation wicri:level="3"><nlm:aff id="JCI61110">Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Suisse</country>
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<author><name sortKey="Debonneville, Anne" sort="Debonneville, Anne" uniqKey="Debonneville A" first="Anne" last="Debonneville">Anne Debonneville</name>
<affiliation wicri:level="3"><nlm:aff id="JCI61110">Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Suisse</country>
<wicri:regionArea>Department of Pharmacology and Toxicology, University of Lausanne, Lausanne</wicri:regionArea>
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<author><name sortKey="Malsure, Sumedha Ram" sort="Malsure, Sumedha Ram" uniqKey="Malsure S" first="Sumedha Ram" last="Malsure">Sumedha Ram Malsure</name>
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<country xml:lang="fr" wicri:curation="lc">Suisse</country>
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<author><name sortKey="Fowler Jaeger, Nicole" sort="Fowler Jaeger, Nicole" uniqKey="Fowler Jaeger N" first="Nicole" last="Fowler-Jaeger">Nicole Fowler-Jaeger</name>
<affiliation wicri:level="3"><nlm:aff id="JCI61110">Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Suisse</country>
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<author><name sortKey="Boase, Natasha A" sort="Boase, Natasha A" uniqKey="Boase N" first="Natasha A." last="Boase">Natasha A. Boase</name>
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<country xml:lang="fr" wicri:curation="lc">Australie</country>
<wicri:regionArea>Department of Hematology, Centre for Cancer Biology, Adelaide</wicri:regionArea>
<wicri:noRegion>Adelaide</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Perrier, Romain" sort="Perrier, Romain" uniqKey="Perrier R" first="Romain" last="Perrier">Romain Perrier</name>
<affiliation wicri:level="3"><nlm:aff id="JCI61110">Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Suisse</country>
<wicri:regionArea>Department of Pharmacology and Toxicology, University of Lausanne, Lausanne</wicri:regionArea>
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<author><name sortKey="Maillard, Marc" sort="Maillard, Marc" uniqKey="Maillard M" first="Marc" last="Maillard">Marc Maillard</name>
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<country xml:lang="fr" wicri:curation="lc">Suisse</country>
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<author><name sortKey="Yang, Baoli" sort="Yang, Baoli" uniqKey="Yang B" first="Baoli" last="Yang">Baoli Yang</name>
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<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa</wicri:regionArea>
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</placeName>
<orgName type="university">Université de l'Iowa</orgName>
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<author><name sortKey="Stokes, John B" sort="Stokes, John B" uniqKey="Stokes J" first="John B." last="Stokes">John B. Stokes</name>
<affiliation wicri:level="4"><nlm:aff id="JCI61110">Department of Internal Medicine, University of Iowa, and VA Medical Center, Iowa City, Iowa, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Internal Medicine, University of Iowa, and VA Medical Center, Iowa City, Iowa</wicri:regionArea>
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</placeName>
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<author><name sortKey="Koesters, Robert" sort="Koesters, Robert" uniqKey="Koesters R" first="Robert" last="Koesters">Robert Koesters</name>
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<country xml:lang="fr" wicri:curation="lc">France</country>
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<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
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<author><name sortKey="Kumar, Sharad" sort="Kumar, Sharad" uniqKey="Kumar S" first="Sharad" last="Kumar">Sharad Kumar</name>
<affiliation wicri:level="1"><nlm:aff id="JCI61110">Department of Hematology, Centre for Cancer Biology, Adelaide, Australia.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Australie</country>
<wicri:regionArea>Department of Hematology, Centre for Cancer Biology, Adelaide</wicri:regionArea>
<wicri:noRegion>Adelaide</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Hummler, Edith" sort="Hummler, Edith" uniqKey="Hummler E" first="Edith" last="Hummler">Edith Hummler</name>
<affiliation wicri:level="3"><nlm:aff id="JCI61110">Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Suisse</country>
<wicri:regionArea>Department of Pharmacology and Toxicology, University of Lausanne, Lausanne</wicri:regionArea>
<placeName><settlement type="city">Lausanne</settlement>
<region nuts="3" type="region">Canton de Vaud</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Loffing, Johannes" sort="Loffing, Johannes" uniqKey="Loffing J" first="Johannes" last="Loffing">Johannes Loffing</name>
<affiliation wicri:level="4"><nlm:aff id="JCI61110">Institute of Anatomy, University of Zurich, Zurich, Switzerland.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Suisse</country>
<wicri:regionArea>Institute of Anatomy, University of Zurich, Zurich</wicri:regionArea>
<orgName type="university">Université de Zurich</orgName>
<placeName><settlement type="city">Zurich</settlement>
<region nuts="3" type="region">Canton de Zurich</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Staub, Olivier" sort="Staub, Olivier" uniqKey="Staub O" first="Olivier" last="Staub">Olivier Staub</name>
<affiliation wicri:level="3"><nlm:aff id="JCI61110">Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Suisse</country>
<wicri:regionArea>Department of Pharmacology and Toxicology, University of Lausanne, Lausanne</wicri:regionArea>
<placeName><settlement type="city">Lausanne</settlement>
<region nuts="3" type="region">Canton de Vaud</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">The Journal of Clinical Investigation</title>
<idno type="ISSN">0021-9738</idno>
<idno type="eISSN">1558-8238</idno>
<imprint><date when="2013">2013</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<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>
</record>

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Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension

Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension

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