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J. Biol. Chem., Vol. 276, Issue 42, 38911-38920, October 19, 2001
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From 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.
Alteration of Cardiac and Renal Functions in Transgenic
Mice Overexpressing Human Mineralocorticoid Receptor*
,
,,, and
INSERM U478, Faculté de
Médecine Xavier Bichat, 75018 Paris, § Service de
cardiologie, Institut Féderatif de Recherche 14, Centre
hospitalier Universitaire Pitié-Salpetrière, 75013 Paris, ¶ Centre d'Explorations Fonctionnelles Integré,
Institut Féderatif de Recherche Claude Bernard, Faculté
de Médecine Xavier Bichat, 75018 Paris, INSERM U426,
Faculté de Médecine Xavier Bichat, 75018 Paris, and
** Service d'Anatomopathologie, Centre hospitalier
Universitaire Xavier Bichat, 75018 Paris, France
*
This work was supported in part by INSERM and by a grant
from the Fondation de France (to M. L.). D. L. is a recipient of a
doctoral fellowship from the Ministère de l'Education Nationale et de la Recherche and a fellowship from the Fondation pour la Recherche Médicale.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: INSERM U478,
faculté de Médecine Xavier Bichat, 16 rue Henri Huchard,
BP416, 75870 Paris, Cedex 18, France. Tel.: 33-1-44-85-63-19; Fax:
33-1-42-29-16-44; E-mail: mlombes@bichat.inserm.fr.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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