Document Detail


Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension.
MedLine Citation:
PMID:  23348737     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-25
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-05-13     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  657-65     Citation Subset:  AIM; IM    
Affiliation:
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
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MeSH Terms
Descriptor/Qualifier:
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:
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:
J Clin Invest. 2013 Feb 1;123(2):546-8   [PMID:  23348731 ]

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