| Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension. | |
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MedLine Citation:
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PMID: 23348737 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Caroline Ronzaud; Dominique Loffing-Cueni; Pierrette Hausel; Anne Debonneville; Sumedha Ram Malsure; Nicole Fowler-Jaeger; Natasha A Boase; Romain Perrier; Marc Maillard; Baoli Yang; John B Stokes; Robert Koesters; Sharad Kumar; Edith Hummler; Johannes Loffing; Olivier Staub |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2013-01-25 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 123 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2013 Feb |
Date Detail:
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Created Date: 2013-04-19 Completed Date: 2013-05-13 Revised Date: 2013-05-20 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 657-65 Citation Subset: AIM; IM |
Affiliation:
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Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blood Pressure Disease Models, Animal Endosomal Sorting Complexes Required for Transport / deficiency*, genetics, metabolism Epithelial Sodium Channels / metabolism Humans Hypertension / etiology*, genetics, physiopathology Kidney Tubules / physiopathology* Liddle Syndrome / etiology, genetics, physiopathology Mice Mice, Knockout Potassium / blood, urine Potassium Channels, Inwardly Rectifying / metabolism Receptors, Drug / metabolism* Sodium / blood, urine Sodium, Dietary / administration & dosage, adverse effects Symporters / metabolism* Ubiquitin-Protein Ligases / deficiency*, genetics, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Endosomal Sorting Complexes Required for Transport; 0/Epithelial Sodium Channels; 0/Kcnj1 protein, mouse; 0/Potassium Channels, Inwardly Rectifying; 0/Receptors, Drug; 0/Slc12a3 protein, mouse; 0/Sodium, Dietary; 0/Symporters; 7440-09-7/Potassium; 7440-23-5/Sodium; EC 6.3.2.19/Nedd4 ubiquitin protein ligases; EC 6.3.2.19/Ubiquitin-Protein Ligases |
| Comments/Corrections | |
Comment In:
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J Clin Invest. 2013 Feb 1;123(2):546-8
[PMID:
23348731
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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