Plasminogen activator inhibitor-1 deficiency protects against aldosterone-induced glomerular injury

This study tests the hypothesis that plasminogen activator inhibitor-1 (PAI-1) contributes to aldosterone-induced renal and cardiac injury. The effects of 12-week aldosterone (2.8 mu g/day)/salt (1% drinking water) versus vehicle/salt on renal and cardiac histology and mRNA expression were determined in wild-type (WT) and PAI-1 deficient (PAI-1((-/-))) mice. Systolic blood pressure was similar in aldosterone-infused WT and PAI-1((-/ -)) mice until 12 weeks, when it was significantly higher in the WT mice. At 12 weeks, urine volume, sodium excretion, and sodium/potassium ratio were similarly increased in the two aldosterone-infused groups. In contrast, urine albumin excretion was greater in aldosterone-infused WT mice (mean +/- s.d.: 699.0 +/- 873.0 mu g/24 h) compared to vehicle-infused WT (23.6 +/- 9.0 mu g/24 h, P = 0.003) or aldosterone-infused PAI-1(()-/-) mice (131.6 +/- 110.6 mu g/24 h, P = 0.007). Aldosterone increased glomerular area to a greater extent in WT (4651 +/- 577 versus 3278 +/- 488 mu m(2)/glomerulus in vehicle-infused WT, P < 0.001) than in PAI-1((-/-)) mice (3713 +/- 705 mu m(2)/glomerulus, P < 0.001 versus aldosterone-infused WT), with corresponding mesangial expansion. Renal collagen content was also increased in aldosterone-infused WT versus PAI-1(( -/-)) mice. In WT mice, aldosterone increased renal mRNA expression of PAI-1, collagen I, collagen III, osteopontin, fibronectin, monocyte chemoattractant protein-1 (MCP-1), and F4/80 (all P < 0.05), but not transforming growth factor beta (TGF-beta). In PAI-1((-/-)) mice, aldosterone increased renal expression of collagen I, osteopontin, fibronectin, and MCP-1, and tended to increase collagen III. Renal osteopontin expression was diminished in aldosterone-treated PAI-1((-/-)) compared to aldosterone-treated WT mice (P = 0.05). Aldosterone induced cardiac hypertrophy but not fibrosis in WT and PAI-1((-/-)) mice. PAI-1 contributes to aldosterone-induced glomerular injury.