Gonzalez Julien, Klein Julie, Chauhan Sharmila D, Neau Eric, Calise Denis, Nevoit Caroline, Chaaya Rana, Miravete Mathieu, Delage Christine, Bascands Jean-Loup, Schanstra Joost P, Buffin-Meyer Bénédicte
INSERM, U858-I2MR - Equipe 5, 1 avenue Jean Poulhès, B.P. 84225, 31432 Toulouse Cedex 4, France.
Exp Biol Med (Maywood). 2009 Dec;234(12):1511-8. doi: 10.3181/0903-RM-105.
We examined the capacity of delayed inhibition of plasminogen activator inhibitor-1 (PAI-1) to reduce tubulointerstitial fibrosis induced by unilateral ureteral obstruction (UUO) in mice. Small peptides mimicking parts of urokinase (uPA) and tissular plasminogen activator (tPA) and serving as decoy molecules for PAI-1 were administered daily during the late stages (3 to 8 days) of UUO. Treatment with PAI-1 decoys reduced interstitial deposition of fibronectin, collagen III and collagen IV without changes in macrophage and myofibroblast infiltration. Interestingly, while PAI-1 activity was reduced and the combined uPA and tPA activity was increased, the antifibrotic effect was obtained without modification of plasmin activity but with increased of hepatocyte growth factor (HGF) expression. We show for the first time that treatment with small PAI-1 decoy peptides reduces established tubulointerstitial fibrosis. This protective effect probably resulted from increased degradation of the extracellular matrix by an HGF dependent mechanism.
我们研究了延迟抑制纤溶酶原激活物抑制剂-1（PAI-1）对减轻小鼠单侧输尿管梗阻（UUO）所致肾小管间质纤维化的能力。在UUO后期（3至8天），每天给予模拟尿激酶（uPA）和组织型纤溶酶原激活物（tPA）部分序列并作为PAI-1诱饵分子的小肽。用PAI-1诱饵进行治疗可减少纤连蛋白、III型胶原和IV型胶原的间质沉积，而巨噬细胞和肌成纤维细胞浸润无变化。有趣的是，虽然PAI-1活性降低，uPA和tPA的联合活性增加，但抗纤维化作用并非通过改变纤溶酶活性获得，而是通过增加肝细胞生长因子（HGF）表达实现。我们首次表明，用小的PAI-1诱饵肽治疗可减轻已形成的肾小管间质纤维化。这种保护作用可能是由HGF依赖性机制增加细胞外基质降解所致。
