Glomerular matrix accumulation is linked to inhibition of the plasmin protease system.
Glomerular matrix accumulation is linked to inhibition of the plasmin protease system.
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DOI：
10.1038/ki.1992.442
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发表时间：
1992-12
影响因子：
19.6
通讯作者：
S. Tomooka;W. A. Border;B. C. Marshall;N. Noble
中科院分区：
文献类型：
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作者：
S. Tomooka;W. A. Border;B. C. Marshall;N. Noble
肾小球基质积累与纤溶酶蛋白酶系统的抑制有关。 TGF-β在实验性肾小球肾炎细胞外基质的病理性积累中发挥着关键作用。 TGF-β表达增加导致细胞外基质成分的合成和沉积增加，而给予TGF-β抗血清可抑制疾病的主要表现。我们假设 TGF-β 还可能通过影响蛋白酶/蛋白酶抑制剂平衡来减少基质周转，从而增强基质积累。纤溶酶是一种有效的蛋白酶，能够降解多种基质分子。纤溶酶原产生的纤溶酶受纤溶酶原激活剂 (PA) 和纤溶酶原激活剂抑制剂 (PAI) 调节。在这项研究中，当将 TGF-β 添加到正常肾小球时，PA 活性显着降低，PAI-1 合成显着增加。患病肾小球还表现出 PA 活性降低、PAI-1 合成增加以及 PAI-1 沉积到基质中增加。给肾小球肾病大鼠施用抗 TGF-β 血清可阻断肾小球 PAI-1 沉积的预期增加。因此，有利于基质积累的 PA/PAI 平衡的变化是由正常肾小球中的 TGF-β 诱导的，并且当内源性 TGF-β 产生较高时，也存在于肾小球中。我们的研究结果表明纤溶酶蛋白酶系统参与急性肾小球损伤后的组织修复，并提出了 TGF-β 增强许多肾小球疾病的基质积累特征的另一种机制。
Glomerular matrix accumulation is linked to inhibition of the plasmin protease system. TGF-β plays a pivotal role in the pathological accumulation of extracellular matrix in experimental glomerulonephritis. Increased TGF-β expression leads to increased synthesis and deposition of extracellular matrix components while administration of antiserum to TGF-β suppresses the major manifestations of the disease. We hypothesized that TGF-β might also enhance matrix accumulation by decreasing matrix turnover via effects on protease/protease inhibitor balance. Plasmin is a potent protease capable of degrading a variety of matrix molecules. Plasmin generation from plasminogen is regulated by plasminogen activator(s) (PA) and plasminogen activator inhibitor(s) (PAI). In this study PA activity was markedly reduced and PAI-1 synthesis dramatically increased when TGF-β was added to normal glomeruli. Diseased glomeruli also showed decreased PA activity, increased PAI-1 synthesis and increased PAI-1 deposition into matrix. Administration of anti-TGF-β serum to glomerulonephritic rats blocked the expected increase in glomerular PAI-1 deposition. Thus changes in the PA/PAI balance favoring accumulation of matrix are induced by TGF-β in normal glomeruli and are present in nephritic glomeruli when endogenous TGF-β production is high. Our findings implicate the plasmin protease system in tissue repair following acute glomerular injury and suggest another mechanism by which TGF-β enhances the matrix accumulation characteristic of many glomerular diseases.