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

J. Ma, A. Weisberg, J. P. Griffin, D. E. Vaughan, A. B. Fogo, N. J. Brown*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

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 μg/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 μg/24 h) compared to vehicle-infused WT (23.6 ± 9.0 μg/24 h, P = 0.003) or aldosterone-infused PAI-1(-/-) mice (131.6 ± 110.6 μg/24 h, P = 0.007). Aldosterone increased glomerular area to a greater extent in WT (4651 ± 577 versus 3278 ± 488 μm 2/glomerulus in vehicle-infused WT, P < 0.001) than in PAI-1 (-/-) mice (3713 ± 705 μm2/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-β). 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.

Original languageEnglish (US)
Pages (from-to)1064-1072
Number of pages9
JournalKidney international
Volume69
Issue number6
DOIs
StatePublished - Mar 2006

Keywords

  • Aldosterone
  • Angiotensin
  • Plasminogen activator inhibitor-1

ASJC Scopus subject areas

  • Nephrology

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