title: Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and prevents oxidative stress in uremic rats.
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.
authors.affiliation: Faculty of Medicine, Universidad Los Andes, S Carlos Apoquindo 2200, Santiago, Chile.
authors.forename: Luis
authors.initials: L
authors.lastname: Michea
authors.forename: Andrea
authors.initials: A
authors.lastname: Villagrán
authors.forename: Alvaro
authors.initials: A
authors.lastname: Urzúa
authors.forename: Sonia
authors.initials: S
authors.lastname: Kuntsmann
authors.forename: Patricio
authors.initials: P
authors.lastname: Venegas
authors.forename: Loreto
authors.initials: L
authors.lastname: Carrasco
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Elisa T
authors.initials: ET
authors.lastname: Marusic
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D006332:Cardiomegaly / Q000517:prevention & control*; D004195:Disease Models, Animal; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009392:Nephrectomy; D018384:Oxidative Stress / Q000187:drug effects*; D011336:Probability; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013148:Spironolactone / Q000494:pharmacology*; D014511:Uremia / Q000503:physiopathology*; D016482:Urinalysis; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D015415:Biomarkers; D017874:Immediate-Early Proteins; D000451:Mineralocorticoid Receptor Antagonists; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000099184:Serum-Glucocorticoid Regulated Kinases