Title: Plasminogen activator inhibitor-1 gene deficiency attenuates TGF-beta1-induced kidney disease
Authors: Krag, Søren ×
Danielsen, Carl Christian
Carmeliet, Peter
Nyengaard, Jens
Wogensen, Lise #
Issue Date: Nov-2005
Series Title: Kidney international vol:68 issue:6 pages:2651-66
Abstract: BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) stimulates the deposition of extracellular matrix (ECM), which is a hallmark in end-stage renal disease. The importance of TGF-beta1-induced changes in protease activity in this process is not fully elucidated. TGF-beta1 up-regulates plasminogen activator inhibitor type 1 (PAI-1), which lowers matrix degradation. Our aim was to investigate the importance of PAI-1 in TGF-beta1-induced kidney disease. METHODS: TGF-beta1 transgenic mice were bred with PAI-1 gene deficient mice. The effect of PAI-1 gene knockout on TGF-beta1-induced glomerular disease was investigated by measuring morphologic changes in the glomeruli. Interstitial changes were assessed by measurement of total collagen content and expression and localization of ECM components. Finally, protease activity was evaluated by plasmin activity measurement and by gel and in situ gelatin zymography. RESULTS: TGF-beta1 elevated PAI-1 expression fourfold. PAI-1 gene deficiency attenuated the TGF-beta1-induced mesangial expansion and basement membrane thickening. Furthermore, PAI-1 knockout diminished collagen accumulation in TGF-beta1-positive mice. The expression of both collagen type I and III were reduced. Interestingly, no difference in protease activity could be ascertained as cause of the decreased ECM accumulation. CONCLUSION: We show that PAI-1 gene deficiency attenuates TGF-beta1-induced kidney disease, decreasing both glomerular and interstitial ECM deposition. Thus, PAI-1 mediates some of the biological effects of TGF-beta1 in vivo. However, we could not find evidence supporting the notion that the effect was mediated through increased protease activity.
ISSN: 0085-2538
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular and Vascular Biology
Laboratory of Angiogenesis and Vascular Metabolism (VIB-KU Leuven Centre for Cancer Biology) (+)
× corresponding author
# (joint) last author

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