Published Online
on June 30, 2008

A more recent version of this article appeared on August 1, 2008

This Article Full Text (PDF) Data Supplement All Versions of this Article: 52/2/295    most recent HYPERTENSIONAHA.107.109645v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Michea, L. Articles by Marusic, E. T. Search for Related Content PubMed PubMed Citation Articles by Michea, L. Articles by Marusic, E. T. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB SPIRONOLACTONE Related Collections Cardio-renal physiology/pathophysiology Remodeling Animal models of human disease Hypertrophy Physiological and pathological control of gene expression Oxidant stress

Submitted on December 31, 2007
Revised on January 17, 2008

Mineralocorticoid Receptor Antagonism Attenuates Cardiac Hypertrophy and Prevents Oxidative Stress in Uremic Rats

Luis Michea; Andrea Villagrán; Alvaro Urzúa; Sonia Kuntsmann; Patricio Venegas; Loreto Carrasco; Magdalena Gonzalez; and Elisa T. Marusic^*

From the Instituto de Ciencias Biomédicas (L.M., L.C., M.G.), Centro Fondo de Investigación Avanzado en Areas Prioritarias Estudios Moleculares de la Célula and Millenium Nucleus on Immunology and Immunotherapy, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Laboratorio de Fisiología Integrativa y Molecular (A.V., A.U., S.K., L.C., E.T.M.), Facultad de Medicina, Universidad Los Andes, Santiago, Chile; and Clínica Las Condes (S.K., P.V.), Santiago, Chile.

^* To whom correspondence should be addressed. E-mail: emarusic{at}uandes.cl.

Abstract—Chronic renal failure causes left ventricular hypertrophy, but the molecular mechanisms involved remain unknown. We, therefore, investigated whether the mineralocorticoid receptor is implicated in the cardiac hypertrophy observed in uremic rats and whether mineralocorticoid receptor blockade could be protective in chronic renal failure. Experimental groups were: control rats, uremic rats (NPX) with 5/6 nephrectomy (5 weeks), and NPX rats fed with spironolactone for 5 weeks. Systolic blood pressure was increased in both NPX rats and NPX rats fed with spironolactone for 5 weeks. Echocardiography revealed concentric left ventricular hypertrophy in uremia, which was attenuated by spironolactone. Enlarged cardiomyocyte size was observed in both left and right ventricles of NPX rats, an effect that was prevented by spironolactone. Mineralocorticoid receptor antagonism attenuated the increase of ventricular brain natriuretic peptide mRNA levels induced by nephrectomy. Left ventricular gene expressions of aldosterone synthase, mineralocorticoid receptor, and hydroxysteroid dehydrogenase type 2 were the same in the 3 groups, whereas gene expression of the glucocorticoid receptor was significantly diminished in chronic renal failure rats. No significant differences in cardiac aldosterone were observed between control rats and NPX rats, although NPX rats fed with spironolactone for 5 weeks showed increased plasma aldosterone levels. However, a significant increase in serum and glucocorticoid-inducible kinase-1 mRNA expression and protein was present in the NPX group; spironolactone treatment significantly reduced serum and glucocorticoid-inducible kinase-1 mRNA and protein in the left ventricle. Uremic rats exhibited a significant increase of superoxide production and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits expression (NOX-2, NOX-4, and p47^phox) in the left ventricle, which was prevented by the mineralocorticoid receptor antagonist. Our findings provide evidence of the beneficial effects of spironolactone in cardiac hypertrophy and cardiac oxidative stress in chronic renal failure.

Key words: aldosterone • mineralocorticoid receptor • cardiac hypertrophy • SGK1 • oxidative stress • hydroxysteroid dehydrogenase type 2

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