title: Aldosterone antagonism or synthase inhibition reduces end-organ damage induced by treatment with angiotensin and high salt.
abstract: In the setting of high salt intake, aldosterone stimulates fibrosis in the heart, great vessels, and kidney of rats. We used uninephrectomized rats treated with angiotensin II and placed on a high salt diet to exaggerate renal fibrosis. We then tested whether mineralocorticoid receptor blockade by spironolactone or aldosterone synthase inhibition by FAD286 have similar effects on end-organ damage and gene expression. Individually, both drugs prevented the hypertensive response to uninephrectomy and high salt intake but not when angiotensin II was administered. Following 4 weeks of treatment with FAD286, plasma aldosterone was reduced, whereas spironolactone increased aldosterone at 8 weeks of treatment. Angiotensin II and high salt treatment caused albuminuria, azotemia, renovascular hypertrophy, glomerular injury, increased plasminogen activator inhibitor-1 (PAI-1), and osteopontin mRNA expression, as well as tubulointerstitial fibrosis in the kidney. Both drugs prevented these renal effects and attenuated cardiac and aortic medial hypertrophy while reducing osteopontin and transforming growth factor-beta mRNA expression in the aorta. The two drugs also reduced cardiac interstitial fibrosis but had no effect on that of the perivascular region. Although spironolactone enhanced angiotensin II and salt-stimulated PAI-1 mRNA expression in aorta and heart, spironolactone and FAD286 prevented renal PAI-1 mRNA protein expression. Our study shows that mineralocorticoid receptor antagonism and aldosterone synthase inhibition similarly decrease hypertrophy and interstitial fibrosis of the kidney and heart caused by angiotensin II and high salt.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Lea
authors.forename: Eun Soo
authors.initials: ES
authors.lastname: Kwak
authors.forename: James M
authors.initials: JM
authors.lastname: Luther
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fowler
authors.forename: Zuofei
authors.initials: Z
authors.lastname: Wang
authors.forename: Ji
authors.initials: J
authors.lastname: Ma
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Brown
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis / Q000188:drug therapy; D006331:Heart Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D051381:Rats; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*; D013148:Spironolactone / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D017673:Sodium Chloride, Dietary; D000804:Angiotensin II; D013148:Spironolactone; D019405:Cytochrome P-450 CYP11B2