Document Detail


Salt-induced hypertension in a mouse model of Liddle syndrome is mediated by epithelial sodium channels in the brain.
MedLine Citation:
PMID:  22802227     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Neural precursor cell expressed and developmentally downregulated 4-2 protein (Nedd4-2) facilitates the endocytosis of epithelial Na channels (ENaCs). Both mice and humans with a loss of regulation of ENaC by Nedd4-2 have salt-induced hypertension. ENaC is also expressed in the brain, where it is critical for hypertension on a high-salt diet in salt-sensitive rats. In the present studies we assessed whether Nedd4-2 knockout (-/-) mice have the following: (1) increased brain ENaC; (2) elevated cerebrospinal fluid (CSF) sodium on a high-salt diet; and (3) enhanced pressor responses to CSF sodium and hypertension on a high-salt diet, both mediated by brain ENaC. Prominent choroid plexus and neuronal ENaC staining was present in -/- but not in wild-type mice. In chronically instrumented mice, ICV infusion of Na-rich artificial CSF increased mean arterial pressure 3-fold higher in -/- than in wild-type mice. ICV infusion of the ENaC blocker benzamil abolished this enhancement. In telemetered -/- mice on a high-salt diet (8% NaCl), CSF [Na(+)], mean arterial pressure, and heart rate increased significantly, mean arterial pressure by 30 to 35 mmHg. These mean arterial pressure and heart rate responses were largely prevented by ICV benzamil but only to a minor extent by SC benzamil at the ICV rate. We conclude that increased ENaC expression in the brain of Nedd4-2 -/- mice mediates their hypertensive response to a high-salt diet by causing increased sodium levels in the CSF, as well as hyperresponsiveness to CSF sodium. These findings highlight the possible causative contribution of central nervous system ENaC in the etiology of salt-induced hypertension.
Authors:
James W Van Huysse; Md Shahrier Amin; Baoli Yang; Frans H H Leenen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-16
Journal Detail:
Title:  Hypertension     Volume:  60     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-08-16     Completed Date:  2013-01-07     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  691-6     Citation Subset:  IM    
Affiliation:
Hypertension Unit, University of Ottawa Heart Institute, 40 Ruskin St, H-3238, Ottawa, Ontario K1Y 4W7, Canada. jvanhuysse@ottawaheart.ca
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MeSH Terms
Descriptor/Qualifier:
Amiloride / analogs & derivatives,  pharmacology
Animals
Blood Pressure / drug effects
Brain / metabolism*
Disease Models, Animal
Endosomal Sorting Complexes Required for Transport / deficiency,  genetics,  metabolism
Epithelial Sodium Channels / drug effects,  metabolism*
Female
Heart Rate / drug effects
Hypertension / chemically induced*,  metabolism*
Liddle Syndrome / metabolism*
Male
Mice
Mice, Knockout
Sodium / cerebrospinal fluid
Sodium Chloride, Dietary / adverse effects*,  pharmacology
Ubiquitin-Protein Ligases / deficiency,  genetics,  metabolism
Grant Support
ID/Acronym/Agency:
MOP 74432//Canadian Institutes of Health Research; P50 DK052617/DK/NIDDK NIH HHS; P50-DK52617/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Endosomal Sorting Complexes Required for Transport; 0/Epithelial Sodium Channels; 0/Sodium Chloride, Dietary; 2609-46-3/Amiloride; 2898-76-2/benzamil; 7440-23-5/Sodium; EC 6.3.2.19/Nedd4 ubiquitin protein ligases; EC 6.3.2.19/Ubiquitin-Protein Ligases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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