Noninhibitory PAI-1 enhances plasmin-mediated matrix degradation both in vitro and in experimental nephritis.

Noninhibitory PAI-1 enhances plasmin-mediated matrix degradation both in vitro and in experimental nephritis. Research Abstract Details 

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Noninhibitory PAI-1 enhances plasmin-mediated matrix degradation both in vitro and in experimental nephritis. Abstract Text:

Y Huang,W A Border,D A Lawrence,N A Noble,

Plasminogen activator inhibitor-type 1 (PAI-1) is thought to be profibrotic by inhibiting plasmin generation, thereby decreasing turnover of pathological extracellular matrix (ECM). A mutant, noninhibitory PAI-1 (PAI-1R) was recently shown by us to increase glomerular plasmin generation and reduce disease in anti-thy-1 nephritis. Here, in vitro and in vivo studies were performed to determine whether enhanced plasmin-dependent ECM degradation underlies the therapeutic effect of PAI-1R. 3H-labeled ECM was produced by rat mesangial cells (MCs). The effect of wild-type PAI-1 (wt-PAI-1) and PAI-1R on ECM degradation by newly plated MCs was measured by the release of 3H into medium. In vivo, anti-thy-1 nephritis was assessed in normal, untreated diseased and PAI-1R treated rats with or without the plasmin/plasminogen inhibitor, tranexamic acid (TA). wt-PAI-1 totally inhibited plasmin generation and reduced ECM degradation by 76% when exogenous plasminogen was added. Although PAI-1R alone had no effect, PAI-1R in the presence of wt-PAI-1 reversed the wt-PAI-1 inhibition of ECM degradation in a time- and dose-dependent manner (P<0.001). Plasmin activity and zymography were consistent with ECM degradation. Plasmin inhibitors: alpha2-antiplasmin, aprotinin, and TA completely blocked PAI-1R's ability to normalize ECM degradation (P<0.001). Consistent with the in vitro results, TA reversed PAI-1R-induced reductions in glomerular fibrin and ECM accumulation. Other measures of disease severity were either unaltered or partially reversed. PAI-1R reduces pathological ECM accumulation, in large part through effectively competing with native PAI-1 thereby restoring plasmin generation and increasing plasmin-dependent degradation of matrix components.

Noninhibitory PAI-1 enhances plasmin-mediated matrix degradation both in vitro and in experimental nephritis. Publishing Authors By Initials

Y Huang,WA Border,DA Lawrence,NA Noble,

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Noninhibitory PAI-1 enhances plasmin-mediated matrix degradation both in vitro and in experimental nephritis. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Kidney international

VOLUME: 70

Page Numbers: 515-22

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ISSN: 0085-2538

DAY: 21

MONTH: 06

YEAR: 2006

Noninhibitory PAI-1 enhances plasmin-mediated matrix degradation both in vitro and in experimental nephritis. Information

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LANGUAGE: eng

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Grant and Affiliation Information for Noninhibitory PAI-1 enhances plasmin-mediated matrix degradation both in vitro and in experimental nephritis.

AFFILIATION: Fibrosis Research Laboratory, Division of Nephrology, University of Utah School of Medicine, Salt Lake City, Utah 84108, USA.

Country: United States

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MEDLINETA: Kidney Int

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