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

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 c...

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Bibliographic Details
Published in:Kidney international 2012-09, Vol.82 (6), p.643-651
Main Authors: Luther, James M., Luo, Pengcheng, Wang, Zuofei, Cohen, Samuel E., Kim, Hyung-Suk, Fogo, Agnes B., Brown, Nancy J.
Format: Article
Language:English
Subjects:
aldosterone
Aldosterone - deficiency
angiotensin
Angiotensin II
Animals
Aorta - drug effects
Aorta - metabolism
Aorta - pathology
Arterial hypertension. Arterial hypotension
Biological and medical sciences
Biomarkers - blood
Biomarkers - urine
Blood and lymphatic vessels
Blood Pressure - drug effects
Cardiology. Vascular system
cardiovascular
Cytochrome P-450 CYP11B2 - deficiency
Cytochrome P-450 CYP11B2 - genetics
Disease Models, Animal
Fibrosis
Gene Expression Regulation
Heart Diseases - chemically induced
Heart Diseases - genetics
Heart Diseases - metabolism
Heart Diseases - pathology
Heart Diseases - prevention & control
hypertension
Inflammation - genetics
Inflammation - metabolism
Kidney Diseases - chemically induced
Kidney Diseases - genetics
Kidney Diseases - metabolism
Kidney Diseases - pathology
Kidney Diseases - prevention & control
Kidney Glomerulus - drug effects
Kidney Glomerulus - metabolism
Kidney Glomerulus - pathology
Kidneys
Medical sciences
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mineralocorticoid Receptor Antagonists - pharmacology
Myocardium - metabolism
Myocardium - pathology
Nephrology. Urinary tract diseases
Receptors, Mineralocorticoid - drug effects
Receptors, Mineralocorticoid - metabolism
renal injury
Renin-Angiotensin System - drug effects
Renin-Angiotensin System - genetics
Sodium Chloride, Dietary
Spironolactone - pharmacology
Time Factors
Urinary system involvement in other diseases. Miscellaneous
Vascular Diseases - chemically induced
Vascular Diseases - genetics
Vascular Diseases - metabolism
Vascular Diseases - pathology
Vascular Diseases - prevention & control
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Summary: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.
ISSN:0085-2538
1523-1755
DOI:10.1038/ki.2012.170