Abstract
Angiotensin II causes cardiovascular injury in part by aldosterone-induced mineralocorticoid receptor activation, and it can also activate the mineralocorticoid receptor in the absence of aldosterone in vitro. Here we tested whether endogenous aldosterone contributes to angiotensin II/salt-induced cardiac, vascular, and renal injury by the mineralocorticoid receptor. Aldosterone synthase knockout mice and wild-type littermates were treated with angiotensin II or vehicle plus the mineralocorticoid receptor antagonist spironolactone or regular diet while drinking 0.9% saline. Angiotensin II/salt caused hypertension in both the knockout and wild-type mice, an effect significantly blunted in the knockout mice. Either genetic aldosterone deficiency or mineralocorticoid receptor antagonism reduced cardiac hypertrophy, aortic remodeling, and albuminuria, as well as cardiac, aortic, and renal plasminogen activator inhibitor-1 mRNA expression during angiotensin II treatment. Mineralocorticoid receptor antagonism reduced angiotensin II/salt-induced glomerular hypertrophy, but aldosterone deficiency did not. Combined mineralocorticoid receptor antagonism and aldosterone deficiency reduced blood urea nitrogen and restored nephrin immunoreactivity. Angiotensin II/salt also promoted glomerular injury through the mineralocorticoid receptor in the absence of aldosterone. Thus, mineralocorticoid antagonism may have protective effects in the kidney beyond aldosterone synthase inhibition.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Aldosterone / deficiency*
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Angiotensin II*
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Animals
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Aorta / drug effects
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Aorta / metabolism
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Aorta / pathology
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Biomarkers / blood
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Biomarkers / urine
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Blood Pressure / drug effects
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Cytochrome P-450 CYP11B2 / deficiency
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Cytochrome P-450 CYP11B2 / genetics
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Disease Models, Animal
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Fibrosis
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Gene Expression Regulation
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Heart Diseases / chemically induced
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Heart Diseases / genetics
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Heart Diseases / metabolism
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Heart Diseases / pathology
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Heart Diseases / prevention & control*
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Inflammation / genetics
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Inflammation / metabolism
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Kidney Diseases / chemically induced
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Kidney Diseases / genetics
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Kidney Diseases / metabolism
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Kidney Diseases / pathology
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Kidney Diseases / prevention & control*
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Kidney Glomerulus / drug effects
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Kidney Glomerulus / metabolism
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Kidney Glomerulus / pathology
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Mice
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Mice, 129 Strain
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Mice, Inbred C57BL
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Mineralocorticoid Receptor Antagonists / pharmacology*
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Myocardium / metabolism
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Myocardium / pathology
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Receptors, Mineralocorticoid / drug effects*
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Receptors, Mineralocorticoid / metabolism
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Renin-Angiotensin System / drug effects
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Renin-Angiotensin System / genetics
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Sodium Chloride, Dietary
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Spironolactone / pharmacology*
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Time Factors
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Vascular Diseases / chemically induced
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Vascular Diseases / genetics
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Vascular Diseases / metabolism
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Vascular Diseases / pathology
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Vascular Diseases / prevention & control*
Substances
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Biomarkers
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Mineralocorticoid Receptor Antagonists
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Receptors, Mineralocorticoid
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Sodium Chloride, Dietary
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Angiotensin II
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Spironolactone
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Aldosterone
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Cytochrome P-450 CYP11B2