Aldosterone deficiency and mineralocorticoid receptor antagonism prevent angiotensin II-induced cardiac, renal, and vascular injury.

Luther JM, Luo P, Wang Z, Cohen SE, Kim HS, Fogo AB, Brown NJ
Kidney Int. 2012 82 (6): 643-51

PMID: 22622494 · PMCID: PMC3434275 · DOI:10.1038/ki.2012.170

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.

MeSH Terms (25)

Aldosterone Angiotensin II Animals Aorta Biomarkers Blood Pressure Cytochrome P-450 CYP11B2 Disease Models, Animal Fibrosis Gene Expression Regulation Heart Diseases Inflammation Kidney Diseases Kidney Glomerulus Mice Mice, 129 Strain Mice, Inbred C57BL Mineralocorticoid Receptor Antagonists Myocardium Receptors, Mineralocorticoid Renin-Angiotensin System Sodium Chloride, Dietary Spironolactone Time Factors Vascular Diseases

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