The effect of mechanical stretch on TGF-beta and extracellular matrix expression in glomerular cells.

我们检测了机械牵张对培养的肾小球系膜细胞各种生长因子和细胞外基质(ECM)成分表达的影响。机械拉伸以时间和伸长依赖的方式刺激转化生长因子-β1和转化生长因子-β3的mRNA表达，细胞几乎以潜伏期的形式分泌大量的转化生长因子-β蛋白，并随着拉伸的增加而增加。牵张还可刺激系膜ECM的主要成分--I型和IV型胶原及纤维连接蛋白的mRNA表达。牵张诱导的ECM表达在很大程度上由牵张诱导的转化生长因子-β的自分泌/旁分泌介导。机械拉伸还可刺激所有的转化生长因子-β亚型、I、II和III型受体的mRNA表达，并且I-标记的转化生长因子-β与每种转化生长因子-β亚型的结合实际上是增加的。机械牵张还能刺激PDGF A链和B链的mRNA表达。酪氨酸激酶抑制剂可抑制牵张诱导的转化生长因子-β基因的表达。抗PDGF中和抗体可部分抑制牵张诱导的细胞外基质和转化生长因子-β的表达。这些结果表明，机械牵张通过酪氨酸激酶依赖的机制上调了系膜细胞的转化生长因子-β受体，并增加了转化生长因子-β的表达/分泌，而机械牵张诱导的PDGF则增强了这种作用，导致了牵张后系膜细胞ECM的高水平表达。结果提示，转化生长因子-β和血小板衍生生长因子在肾小球高血压肾小球硬化的发病过程中可能起重要作用。

We examined the effect of mechanical stretch on the expression of various growth factors and extracellular matrix(ECM)components in cultured glomerular mesangial cells. Mechanical stretch stimulated mRNA expression of TGF-beta1 and TGF-beta3 in a time- and elongation-dependent manner, and the cells secreted substantial amounts of TGF-beta proteins almost as a latent form, which was increased in response to stretch. Stretch also stimulated mRNA expression of collagen types I and IV,and fibronectin, major components of mesangial ECM.The stretch-induced ECM expression was largely mediated by autocrine/paracrine secretion of TGF-beta induced by stretch. Mechanical stretch also stimulated mRNA expression of all TGF-betaR isoforms, type I,II and III receptors and the binding of ^<125>I-labeled TGF-beta to each TGF-betaR isoform was actually increased by stretch. Mechanical stretch also stimulated mRNA expression of PDGF A- and B-chain. The stretch-induced mRNA expression of TGF-beta was inhibited by tyrosine kinase inhibitors. Moreover, the stretchinduced ECM and TGF-beta expression was both partially inhibited by anti-PDGF neutralizing antibody. These results show that mechanical stretch upregulates TGF-beta receptors and increases TGF-beta expression/secretion through tyrosine kinase-dependent mechanisms, which is enhanced by the stetch-induced PDGF,resulting in high levels of ECM expression after stretch in cultured mesangial cells. The results suggest that TGF-beta and PDGF may play an important role in the progression of glomerulosclerosis by glomerular hypertension in vivo.