Tomooka S, Border W A, Marshall B C, Noble N A
Division of University of Utah School of Medicine, Salt Lake City.
Kidney Int. 1992 Dec;42(6):1462-9. doi: 10.1038/ki.1992.442.
TGF-beta plays a pivotal role in the pathological accumulation of extracellular matrix in experimental glomerulonephritis. Increased TGF-beta expression leads to increased synthesis and deposition of extracellular matrix components while administration of anti-serum to TGF-beta suppresses the major manifestations of the disease. We hypothesized that TGF-beta 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-beta 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-beta 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-beta in normal glomeruli and are present in nephritic glomeruli when endogenous TGF-beta production is high. Our findings implicate the plasmin protease system in tissue repair following acute glomerular injury and suggest another mechanism by which TGF-beta enhances the matrix accumulation characteristic of many glomerular diseases.
转化生长因子-β（TGF-β）在实验性肾小球肾炎细胞外基质的病理性积聚中起关键作用。TGF-β表达增加会导致细胞外基质成分的合成和沉积增加，而给予TGF-β抗血清可抑制该疾病的主要表现。我们推测，TGF-β也可能通过影响蛋白酶/蛋白酶抑制剂平衡来减少基质周转，从而增强基质积聚。纤溶酶是一种能够降解多种基质分子的强效蛋白酶。纤溶酶原生成纤溶酶受纤溶酶原激活物（PA）和纤溶酶原激活物抑制剂（PAI）调控。在本研究中，当向正常肾小球添加TGF-β时，PA活性显著降低，PAI-1合成急剧增加。患病肾小球也表现出PA活性降低、PAI-1合成增加以及PAI-1向基质中的沉积增加。给肾小球肾炎大鼠注射抗TGF-β血清可阻断肾小球PAI-1沉积预期的增加。因此，PA/PAI平衡的变化有利于基质积聚，这是由TGF-β在正常肾小球中诱导产生的，并且当内源性TGF-β产生较高时存在于肾炎性肾小球中。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，并提示了TGF-β增强许多肾小球疾病特征性基质积聚的另一种机制。
