Malliaros J, Holdsworth S R, Wojta J, Erlich J, Tipping P G
Monash University, Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
Kidney Int. 1993 Sep;44(3):557-64. doi: 10.1038/ki.1993.281.
Fibrin is an important mediator of injury in severe proliferative forms of glomerulonephritis (GN). Normal glomeruli express fibrinolytic activity, which may protect against the injurious effects of fibrin deposition. Changes in glomerular fibrinolytic activity (GFA) may play an important role in modulating fibrin accumulation in GN. To study the changes in GFA associated with fibrin deposition in GN, autologous phase anti-glomerular basement antibody initiated GN (anti-GBM GN) was studied in rabbits. Net GFA was significantly reduced in association with glomerular fibrin deposition (1.3 +/- 0.8 ng fibrin lysed/10(3) glomeruli/2 hr, normal 57.1 +/- 25.4 ng fibrin lysed/10(3) glomeruli/2 hr, P < 0.02). Reduced GFA in fibrin associated GN was associated with decreased expression of tissue type plasminogen activator (tPA) and increased expression of plasminogen activator inhibitor type-1 (PAI-1) and glomerular macrophage infiltration. In a fibrin independent model of anti-GBM induced GN (heterologous phase), with equivalent injury (proteinuria), net GFA was increased (174 +/- 64 ng fibrin lysed/10(3) glomeruli/2 hr). This was associated with increased tPA and uPA, and decreased PAI-1 in the absence of significant macrophage infiltration. These studies demonstrate that fibrin deposition in GN is associated with a net reduction of GFA, attributable to reduced expression of plasminogen activators and augmentation of PAI-1. Reduction of GFA may potentiate glomerular fibrin deposition and consequent glomerular injury. The association between glomerular macrophage influx and reduction in GFA suggests that this change may be directed by macrophages.
纤维蛋白是严重增殖型肾小球肾炎（GN）损伤的重要介质。正常肾小球具有纤维蛋白溶解活性，这可能对纤维蛋白沉积的损伤作用起到保护作用。肾小球纤维蛋白溶解活性（GFA）的变化可能在调节GN中纤维蛋白的积聚方面发挥重要作用。为了研究与GN中纤维蛋白沉积相关的GFA变化，在兔中研究了自体期抗肾小球基底膜抗体引发的GN（抗GBM GN）。与肾小球纤维蛋白沉积相关的净GFA显著降低（1.3±0.8 ng纤维蛋白溶解/10³个肾小球/2小时，正常为57.1±25.4 ng纤维蛋白溶解/10³个肾小球/2小时，P<0.02）。纤维蛋白相关GN中GFA降低与组织型纤溶酶原激活物（tPA）表达降低、纤溶酶原激活物抑制剂1型（PAI-1）表达增加以及肾小球巨噬细胞浸润有关。在抗GBM诱导的GN的纤维蛋白非依赖性模型（异源期）中，具有等效损伤（蛋白尿）时，净GFA增加（174±64 ng纤维蛋白溶解/10³个肾小球/2小时）。这与tPA和尿激酶型纤溶酶原激活物（uPA）增加以及PAI-1降低相关，且无明显巨噬细胞浸润。这些研究表明，GN中的纤维蛋白沉积与GFA的净减少相关，这归因于纤溶酶原激活物表达降低和PAI-1增加。GFA降低可能会增强肾小球纤维蛋白沉积及随之而来的肾小球损伤。肾小球巨噬细胞流入与GFA降低之间的关联表明这种变化可能由巨噬细胞介导。
