Document Detail


Alteration of cardiac and renal functions in transgenic mice overexpressing human mineralocorticoid receptor.
MedLine Citation:
PMID:  11495902     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The mineralocorticoid receptor (MR), a ligand-dependent transcription factor, mediates aldosterone actions in a large variety of tissues. To explore the functional implication of MR in pathophysiology, transgenic mouse models were generated using the proximal human MR (hMR) promoter to drive expression of hMR in aldosterone target tissues. Tissue-specific analysis of transgene expression in two independent transgenic animal (TG) lines by ribonuclease protection assays revealed that hMR is expressed in all mineralocorticoid-sensitive tissues, most notably in the kidney and the heart. TG exhibit both renal and cardiac abnormalities. Enlarged kidneys were histologically associated with renal tubular dilation and cellular vacuolization whose prevalence increased with aging. Renal clearance studies also disclosed a significant decrease in urinary potassium excretion rate in TG. hMR-expressing animals had normal blood pressure but developed mild dilated cardiomyopathy (increased left ventricle diameters and decreased shortening fraction), which was accompanied by a significant increase in heart rate. Differential gene expression analysis revealed a 2- to 5-fold increase in cardiac expression of atrial natriuretic peptide, serum- and glucocorticoid-induced kinase, and early growth response gene 1 as detected by microarrays; renal serum- and glucocorticoid-induced kinase was also induced significantly. Altogether, TG exhibited specific alteration of renal and cardiac functions, thus providing useful pathophysiological models to gain new insights into the tissue-specific mineralocorticoid signaling pathways.
Authors:
D Le Menuet; R Isnard; M Bichara; S Viengchareun; M Muffat-Joly; F Walker; M C Zennaro; M Lombès
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2001-08-08
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  276     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2001 Oct 
Date Detail:
Created Date:  2001-10-15     Completed Date:  2001-12-04     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  38911-20     Citation Subset:  IM    
Affiliation:
INSERM U478, Faculté de Médecine Xavier Bichat, 75018 Paris, Service de cardiologie, Institut Féderatif de Recherche 14, Centre hospitalier Universitaire Pitié-Salpetrière, 75013 Paris, France.
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MeSH Terms
Descriptor/Qualifier:
Animals
Blotting, Northern
DNA, Complementary / metabolism
DNA-Binding Proteins / biosynthesis
Early Growth Response Protein 1
Heart / physiology*
Humans
Immediate-Early Proteins*
Kidney / metabolism,  physiology*
Male
Mice
Mice, Transgenic*
Models, Genetic
Myocardium / metabolism
Nuclear Proteins*
Oligonucleotide Array Sequence Analysis
Promoter Regions, Genetic
Protein-Serine-Threonine Kinases / biosynthesis
Receptors, Mineralocorticoid / biosynthesis*,  genetics
Recombinant Proteins / metabolism
Signal Transduction
Sodium-Potassium-Exchanging ATPase / biosynthesis
Time Factors
Tissue Distribution
Transcription Factors / biosynthesis
Chemical
Reg. No./Substance:
0/DNA, Complementary; 0/DNA-Binding Proteins; 0/EGR1 protein, human; 0/Early Growth Response Protein 1; 0/Egr1 protein, mouse; 0/Immediate-Early Proteins; 0/Nuclear Proteins; 0/Receptors, Mineralocorticoid; 0/Recombinant Proteins; 0/Transcription Factors; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/serum-glucocorticoid regulated kinase; EC 3.6.3.9/Sodium-Potassium-Exchanging ATPase

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