Alteration of cardiac and renal functions in transgenic mice overexpressing human mineralocorticoid receptor.
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.
Le Menuet
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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.
Isnard
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R
Bichara
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Viengchareun
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Muffat-Joly
M
M
Walker
F
F
Zennaro
M C
MC
Lombès
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M
D000818:Animals; D015152:Blotting, Northern; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D051766:Early Growth Response Protein 1; D006321:Heart / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins; D007668:Kidney / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009206:Myocardium / Q000378:metabolism; D009687:Nuclear Proteins; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D018161:Receptors, Mineralocorticoid / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000096:biosynthesis; D013997:Time Factors; D014018:Tissue Distribution; D014157:Transcription Factors / Q000096:biosynthesis; D000099184:Serum-Glucocorticoid Regulated Kinases
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D018161:Receptors, Mineralocorticoid; D011994:Recombinant Proteins; D000254:Sodium-Potassium-Exchanging ATPase; D014157:Transcription Factors; D000099184:Serum-Glucocorticoid Regulated Kinases; C497325:EGR1 protein, human; C486109:Egr1 protein, mouse