title: Multifunctionality of PAI-1 in fibrogenesis: evidence from obstructive nephropathy in PAI-1-overexpressing mice.
abstract: BACKGROUND
  Plasminogen activator inhibitor-1 (PAI-1) has been implicated in the pathogenesis of chronic kidney disease based on its up-regulated expression and on the beneficial effects of PAI-1 inhibition or depletion in experimental models. PAI-1 is a multifunctional protein and the mechanisms that account for its profibrotic effects have not been fully elucidated.
  
  
  METHODS
  The present study was designed to investigate PAI-1-dependent fibrogenic pathways by comparing the unilateral ureteral obstruction model (UUO) (days 3, 7, and 14) in PAI-1-overexpressing mice (PAI-1 tg) to wild-type mice, both on a C57BL6 background.
  
  
  RESULTS
  Following UUO, total kidney PAI-1 mRNA and/or protein levels were significantly higher in the PAI-1 tg mice (N= 6 to 8/group) and fibrosis severity was significantly worse (days 3, 7, and 14), measured both as Sirius red-positive interstitial area (e.g., 10 +/- 3.2% vs. 4.5 +/- 1.0%) (day 14) and total kidney collagen (e.g., 11.1 +/- 1.7 vs. 6.2 +/- 1.3 microg/mg) (day 14). By day 14, the expression of two normal tubular proteins, E-cadherin and Ksp-cadherin, were significantly lower in the PAI-1 tg mice (3.2 +/- 0.5% vs. 11.7 +/- 5.9% and 2.6 +/- 1.6) vs. 6.2 +/- 0.8%, respectively), implying more extensive tubular damage. At least four fibrogenic pathways were differentially expressed in the PAI-1 tg mice. First, interstitial macrophage recruitment was more intense (P < 0.05 days 3 and 14). Second, interstitial myofibroblast density was greater (P < 0.05 days 3 and 7) despite similar numbers of proliferating tubulointerstitial cells. Third, transforming growth factor-beta1 (TGF-beta1) and collagen I mRNA were significantly higher. Finally, urokinase activity was significantly lower (P < 0.05 days 7 and 14) despite similar mRNA levels. Gene microarray studies documented that that the deletion of this single profibrotic gene had far-reaching consequences on renal cellular responses to chronic injury.
  
  
  CONCLUSIONS
  These data provide further evidence that PAI-1 is directly involved in interstitial fibrosis and tubular damage via two primary overlapping mechanisms: early effects on interstitial cell recruitment and late effects associated with decreased urokinase activity.
authors.affiliation: Children's Hospital and Regional Medical Center and Department of Pediatrics, University of Washington, Seattle, Washington 98105, USA.
authors.forename: Shunya
authors.initials: S
authors.lastname: Matsuo
authors.forename: Jesús M
authors.initials: JM
authors.lastname: López-Guisa
authors.forename: Xiaohe
authors.initials: X
authors.lastname: Cai
authors.forename: Daryl M
authors.initials: DM
authors.lastname: Okamura
authors.forename: Charles E
authors.initials: CE
authors.lastname: Alpers
authors.forename: Roger E
authors.initials: RE
authors.lastname: Bumgarner
authors.forename: Mette A
authors.initials: MA
authors.lastname: Peters
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Zhang
authors.forename: Allison A
authors.initials: AA
authors.lastname: Eddy
mesh_terms: D000818:Animals; D005355:Fibrosis; D020869:Gene Expression Profiling; D005838:Genotype; D007668:Kidney / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009395:Nephritis, Interstitial / Q000209:etiology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000502:physiology*; D011347:Procollagen / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D011347:Procollagen; D012333:RNA, Messenger; D014568:Urokinase-Type Plasminogen Activator