title: Plasminogen activator inhibitor-1 deficiency protects against aldosterone-induced glomerular injury.
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 microg/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 microg/24 h) compared to vehicle-infused WT (23.6+/-9.0 microg/24 h, P=0.003) or aldosterone-infused PAI-1(-/-) mice (131.6+/-110.6 microg/24 h, P=0.007). Aldosterone increased glomerular area to a greater extent in WT (4651+/-577 versus 3278+/-488 microm2/glomerulus in vehicle-infused WT, P<0.001) than in PAI-1(-/-) mice (3713+/-705 microm2/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.
authors.affiliation: Division of Pediatric Nephrology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6602, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.forename: A
authors.initials: A
authors.lastname: Weisberg
authors.forename: J P
authors.initials: JP
authors.lastname: Griffin
authors.forename: D E
authors.initials: DE
authors.lastname: Vaughan
authors.forename: A B
authors.initials: AB
authors.lastname: Fogo
authors.forename: N J
authors.initials: NJ
authors.lastname: Brown
mesh_terms: D000419:Albuminuria / Q000652:urine; D000450:Aldosterone / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D018932:Chemokine CCL2 / Q000032:analysis / Q000235:genetics; D003094:Collagen / Q000032:analysis / Q000235:genetics; D005353:Fibronectins / Q000032:analysis / Q000235:genetics; D015870:Gene Expression; D005921:Glomerulonephritis / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control* / Q000652:urine; D006439:Hemodynamics / Q000502:physiology; D007678:Kidney Glomerulus / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D009392:Nephrectomy; D053495:Osteopontin; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D012795:Sialoglycoproteins / Q000032:analysis / Q000235:genetics; D012964:Sodium / Q000652:urine
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D005353:Fibronectins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D000450:Aldosterone; D003094:Collagen; D012964:Sodium