Abstract | BACKGROUND: METHODS: 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 = 0.016 vs. placebo) and AT1RA virtually abolished (P = 0.001 vs. placebo) the development of sclerosis. Spironolactone significantly decreased PAI-1 mRNA expression in the kidneys of radiated animals (PAI-1 mRNA/GAPDH ratio 0.39 +/- 0.13 vs. placebo 0.84 +/- 0.05, P = 0.006), and there was a significant correlation between the degree of sclerosis and the level of PAI-1 immunostaining within individual rats (R2 = 0.97, P < 0.0001). CONCLUSION: This study is, to our knowledge, the first to demonstrate that aldosterone regulates PAI-1 expression in vivo, and supports the hypothesis that aldosterone induces renal injury through its effects on PAI-1 expression.
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Authors | N J Brown, S Nakamura, L Ma, I Nakamura, E Donnert, M Freeman, D E Vaughan, A B Fogo |
Journal | Kidney international
(Kidney Int)
Vol. 58
Issue 3
Pg. 1219-27
(Sep 2000)
ISSN: 0085-2538 [Print] United States |
PMID | 10972684
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Mineralocorticoid Receptor Antagonists
- Plasminogen Activator Inhibitor 1
- RNA, Messenger
- Angiotensin II
- Spironolactone
- Aldosterone
- Creatinine
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Topics |
- Aldosterone
(blood)
- Angiotensin II
(physiology)
- Animals
- Blood Pressure
- Blotting, Northern
- Creatinine
(blood)
- Disease Progression
- Fibrosis
- Gene Expression
(drug effects)
- Glomerulosclerosis, Focal Segmental
(drug therapy, pathology, physiopathology)
- In Situ Hybridization
- Kidney Glomerulus
(chemistry, pathology)
- Male
- Mineralocorticoid Receptor Antagonists
(pharmacology)
- Plasminogen Activator Inhibitor 1
(analysis, genetics)
- Proteinuria
(drug therapy, pathology, physiopathology)
- RNA, Messenger
(analysis)
- Rats
- Rats, Sprague-Dawley
- Spironolactone
(pharmacology)
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