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- Title
Aldosterone modulates plasminogen activator inhibitor-1 and glomerulosclerosis in vivo.
- Authors
Brown, Nancy J.; Nakamura, Shinya; Ma, Lijun; Nakamura, Ikuko; Donnert, Ellen; Freeman, Michael; Vaughan, Douglas E.; Fogo, Agnes B.
- Abstract
Aldosterone modulates plasminogen activator inhibitor-1 and glomerulosclerosis in vivo. Background. Aldosterone promotes nephrosclerosis in several rat models, whereas aldosterone receptor antagonism blunts the effect of activation of the renin-angiotensin-aldosterone system (RAAS) on nephrosclerosis, independent of effects on blood pressure. Based on recent findings linking activation of the RAAS with impaired fibrinolytic balance, we hypothesized that aldosterone induces sclerosis through effects on plasminogen activator inhibitor-1 (PAI-1), the major physiological inhibitor of plasminogen activation. Methods. We examined the effect of aldosterone antagonism on the development of sclerosis and on renal PAI-1 expression following radiation injury in the rat. Following a single dose of 12 Gy to the kidneys, male Sprague-Dawley rats were treated with placebo, the aldosterone antagonist spironolactone (4.5 mg/day by time-release subcutaneous pellet), the angiotensin type 1 receptor antagonist L158-809 (AT1RA; 80 mg/L drinking water), or combined spironolactone and AT1RA. Results. Rats treated with placebo developed significant proteinuria and nephrosclerosis 12 weeks following radiation associated with hypertension. Kidney PAI-1 mRNA expression was increased eightfold (P < 0.001 vs. nonradiated controls). Spironolactone alone had no effect on blood pressure (systolic blood pressure 149.0 ± 5.4 mm Hg) compared with placebo (151.6 ± 11.2 mm Hg, P = NS), whereas AT1RA alone (107.7 ± 8.9 mm Hg, P = 0.013 vs. placebo) or in combination therapy (102.1 ± 6.2 mm Hg, P = 0.001 vs. placebo) lowered blood pressure. Both the AT1RA and spironolactone decreased proteinuria following radiation (P < 0.001 vs. placebo for either drug), and the combination of AT1RA + spironolactone had a greater effect on proteinuria than spironolactone alone (P = 0.003). Aldosterone antagonism significantly decreased (P =...
- Subjects
ALDOSTERONE; KIDNEY glomerulus; PLACEBOS
- Publication
Kidney International, 2000, Vol 58, Issue 3, p1219
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1046/j.1523-1755.2000.00277.x