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 = 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).


CONCLUSIONS
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.
Brown
N J
NJ
Departments of Medicine and Pharmacology, Pathology, and Radiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. nancy.brown@mcmail.vanderbilt.edu
Nakamura
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D000450:Aldosterone / Q000097:blood*; D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D001794:Blood Pressure; D015152:Blotting, Northern; D003404:Creatinine / Q000097:blood; D018450:Disease Progression; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D017403:In Situ Hybridization; D007678:Kidney Glomerulus / Q000737:chemistry / Q000473:pathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000235:genetics*; D011507:Proteinuria / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013148:Spironolactone / Q000494:pharmacology*
D000451:Mineralocorticoid Receptor Antagonists; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D000804:Angiotensin II; D013148:Spironolactone; D000450:Aldosterone; D003404:Creatinine