Transforming growth factor-beta is a potent inhibitor of extracellular matrix degradation by cultured human mesangial cells.
Transforming growth factor-beta is a potent inhibitor of extracellular matrix degradation by cultured human mesangial cells.
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发表时间：
1999-04
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通讯作者：
W. Baricos;S. Cortez;Michael Deboisblanc;Shi Xin
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作者：
W. Baricos;S. Cortez;Michael Deboisblanc;Shi Xin
肾小球细胞外基质（ECM）的积累是急性肾小球损伤发展为终末期肾病的关键事件。虽然增强的ECM合成已被证明有助于ECM积累，但减少ECM降解的作用在很大程度上是未知的。先前的研究表明，肾小球ECM的降解是由纤溶酶原激活物(PA)/纤溶酶原/基质金属蛋白酶2 （MMP-2）级联介导的。然而，关于在正常或病理状态下调节这种降解级联活性的因素的信息很少。转化生长因子- β 1 （tgf - β 1）是培养的人系膜细胞降解ECM的有效抑制剂。使用在125i标记的Matrigel薄膜上生长的人系膜细胞，观察到TGF-beta1存在下对ECM降解的剂量依赖性抑制，当TGF-beta1浓度为0.4 ng/ml时，抑制率可达90%。在没有外源性tgf - β的情况下，添加抗tgf - β抗体（4微克/毫升）可增加ECM降解（比对照组增加1.8+/-0.2倍，P<0.05）。相比之下，血小板衍生生长因子在浓度高达10 ng/ml时，对ECM降解没有影响。tgf - β完全阻断纤溶酶原向纤溶酶的转化，并显著降低潜伏型MMP-2向活性型MMP-2的转化。tgf - β没有显著改变组织中PA、总MMP-2或金属蛋白酶-1组织抑制剂的水平，但增加了PA的主要生理抑制剂PA抑制剂-的水平（1.8倍，P<0.05）。这些数据表明，tgf - β是培养的人系膜细胞降解ECM的有效抑制剂，它们表明，由tgf - β介导的PA/plasmin/MMP-2级联活性降低引起的系膜基质降解减少可能导致肾小球基质积累，发生在进行性肾脏疾病中。
Accumulation of the glomerular extracellular matrix (ECM) is a pivotal event in the progression from acute glomerular injury to end-stage renal disease. Although enhanced ECM synthesis has been demonstrated to contribute to ECM accumulation, the role of decreased ECM degradation is largely unknown. It was previously shown that glomerular ECM degradation is mediated by a plasminogen activator (PA)/plasmin/matrix metalloproteinase 2 (MMP-2) cascade. However, little information is available regarding the factors that regulate the activity of this degradative cascade in normal or pathologic states. Transforming growth factor-beta1 (TGF-beta1) is shown here to be a potent inhibitor of ECM degradation by cultured human mesangial cells. Using human mesangial cells grown on thin films of 125I-labeled Matrigel, dose-dependent inhibition of ECM degradation in the presence of TGF-beta1 was observed, reaching >90% inhibition with 0.4 ng/ml TGF-beta1. Addition of anti-TGF-beta antibodies (4 microg/ml) in the absence of exogenous TGF-beta increased ECM degradation (1.8+/-0.2-fold versus controls, P<0.05). In contrast, platelet-derived growth factor, at concentrations up to 10 ng/ml, had no effect on ECM degradation. TGF-beta completely blocked the conversion of plasminogen to plasmin and markedly reduced the conversion of latent MMP-2 to active MMP-2. TGF-beta did not significantly alter the levels of tissue PA, total MMP-2, or tissue inhibitor of metalloproteinase-1, but did increase the levels of PA inhibitor- (1.8-fold, P<0.05), the major physiologic inhibitor of PA. These data document that TGF-beta is a potent inhibitor of ECM degradation by cultured human mesangial cells, and they suggest that decreased mesangial matrix degradation, caused by TGF-beta-mediated decreases in the activity of the PA/plasmin/MMP-2 cascade, may contribute to the glomerular matrix accumulation that occurs in progressive renal disease.