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. 2011 Jun 1;510(1):19-26.
doi: 10.1016/j.abb.2011.04.001. Epub 2011 Apr 9.

Plasminogen activator inhibitor-1 deficient mice are protected from angiotensin II-induced fibrosis

Juliane I Beier  1 , J Phillip Kaiser, Luping Guo, Manuel Martínez-Maldonado, Gavin E Arteel
Affiliations

Plasminogen activator inhibitor-1 deficient mice are protected from angiotensin II-induced fibrosis

Juliane I Beier et al. Arch Biochem Biophys. .

Abstract

PAI-1 has been shown to be both profibrotic and antifibrotic in animal models of hepatic fibrosis. Although these models have similarities to human fibrotic liver disease, no rodent model completely recapitulates the clinical situation; indeed, transaminase values in most models of hepatic fibrosis are much higher than in chronic liver diseases in humans. Here, wild-type and PAI-1(-/-) mice were administered AngII (500 ng/kg/min) for 4 weeks. ECM accumulation was evaluated by Sirius red staining, hydroxyproline content, and fibrin and collagen immunostaining. Induction of pro-fibrotic genes was assessed by real-time RT-PCR. Despite the absence of any significant liver damage, AngII infusion increased the deposition of hepatic collagen and fibrin ECM, with a perisinusoidal pattern. PAI-1(-/-) mice were protected from these ECM changes, indicating a causal role of PAI-1 in this fibrosis model. Protection in the knockout strain correlated with a blunted increase in αSMA, and elevated activities of matrix metalloproteinases (MMP2, MMP9). These data suggest that PAI-1 plays a critical role in mediating fibrosis caused by AngII and lends weight-of-evidence to a pro-fibrotic role of this protein in liver. Furthermore, the current study proposes a new model of 'pure' hepatic fibrosis in mice with little inflammation or hepatocyte death.

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Figures

Figure 1
Figure 1. Photomicrographs of livers after 4 weeks of AngII administration
Mice were treated as described in Materials and Methods. Representative photomicrographs of Sirius Red (200×, inset 400× left) and immunofluorescent collagen type I (Col type I, 200×, insets 400× middle) stains are shown. For immunofluorescent detection of hepatic fibrin (green) against a blue nuclear stain (400×, right), representative confocal photomicrographs are shown.
Figure 2
Figure 2. Effect AngII on indices of hepatic fibrosis in liver
Mice were treated as described in Materials and Methods. Image analysis of Sirius Red positive staining (A) and colorimetric quantitation of hydroxyproline (OH-pro) content in liver tissue (B) are shown. Quantitative data are means ± SEM (n= 4–7) and are expressed as % of microscope field for Sirius Red and as µg/mg tissue for hydroxyproline. a, p < 0.05 compared to saline; b, p < 0.05 compared to wild-type animals + AngII.
Figure 3
Figure 3. Effect of AngII on indices of hepatic inflammation
Mice were treated as described in Materials and Methods. Panels A and B depict results for circulating levels of PAI-1 and TNFα in plasma. Panel C shows hepatic mRNA expression of F4/80. Quantitative data are means ± SEM (n = 4–7) and are expressed as pg/ml or ng/ml plasma for PAI-1 and TNFα respectively and as fold of control for F4/80 expression. a, p < 0.05 compared to saline; b, p < 0.05 compared to wild-type animals + AngII.
Figure 4
Figure 4. Effect of angiotensin on the expression of pro-fibrotic genes
Mice were treated and Real-time RT-PCR for αSMA (A), COL Iα1 (B), P4Hα (C) and TIMP-1 (D) was performed as described in Materials and Methods. Quantitative data are means ± SEM (n = 4–7) and are expressed as fold of control. a, p < 0.05 compared to saline; b, p < 0.05 compared to wild-type animals + AngII.
Figure 5
Figure 5. Hepatic uPA/tPA and MMP activity after AngII
Mice were treated and zymography was performed as described in Materials and Methods. Panel A shows representative zymography bands from the same gel, while Panel B depicts respective summary results of image analysis of gelatinase activity. Quantitative data are means ± SEM (n = 4–7) and are expressed as fold of control. a, p < 0.05 compared to saline; b, p < 0.05 compared to wild-type animals + AngII.
Figure 6
Figure 6. Effect of AngII on markers of angiogenesis
Mice were treated and Real-time RT-PCR was performed as described in Materials and Methods. Panel A: Representative confocal photomicrographs (400×) depicting immunofluorescent detection of hepatic CD31 against a DAPI nuclear stain are shown. Panel B: Real-time RT-PCR for CD31 and Tie2. Quantitative data are means ± SEM (n = 4–7) and are expressed as fold of control. a, p < 0.05 compared to saline; b, p < 0.05 compared to wild-type animals + AngII.
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