title: Aldosterone deficiency and mineralocorticoid receptor antagonism prevent angiotensin II-induced cardiac, renal, and vascular injury.
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.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. James.Luther@Vanderbilt.edu
authors.forename: James M
authors.initials: JM
authors.lastname: Luther
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Luo
authors.forename: Zuofei
authors.initials: Z
authors.lastname: Wang
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Cohen
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Brown
mesh_terms: D000450:Aldosterone / Q000172:deficiency*; D000804:Angiotensin II; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001794:Blood Pressure / Q000187:drug effects; D019405:Cytochrome P-450 CYP11B2 / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D005355:Fibrosis; D005786:Gene Expression Regulation; D006331:Heart Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018161:Receptors, Mineralocorticoid / Q000187:drug effects* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics; D017673:Sodium Chloride, Dietary; D013148:Spironolactone / Q000494:pharmacology*; D013997:Time Factors; D014652:Vascular Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D015415:Biomarkers; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D000804:Angiotensin II; D013148:Spironolactone; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2