Hirakata M, Kaname S, Chung U G, Joki N, Hori Y, Noda M, Takuwa Y, Okazaki T, Fujita T, Katoh T, Kurokawa K
Department of Internal Medicine, University of Tokyo School of Medicine, Japan.
Kidney Int. 1997 Apr;51(4):1028-36. doi: 10.1038/ki.1997.144.
Increased glomerular hydraulic pressure has been suggested as a major causative factor in the development of glomerular sclerosis. The elevation of glomerular pressure increases the magnitude of stretch to mesangial cells. The study was, therefore, designed to investigate the effect of mechanical stretch on expression of TGF-beta and extracellular matrix components in cultured rat mesangial cells. The results showed that mechanical stretch stimulated mRNA expression for TGF-beta1 and TGF-beta3 in a time dependent manner, and that mesangial cells secreted substantial amounts of TGF-beta proteins in response to stretch. Stretch was also shown to stimulate mRNA expression for collagen types I and IV, and fibronectin, major components of mesangial extracellular matrix. The stretch-induced mRNA expression for extracellular matrix components was inhibited by neutralizing antibody to TGF-beta. Moreover, stretch-induced mRNA expression of TGF-beta was inhibited by tyrosine kinase inhibitors, genistein or herbimycin A, whereas Ca channel blockers nitrendipine or Gd3+, and inhibitors for protein kinase A or C had no effect. These findings indicate that stretch induced TGF-beta mRNA primarily through tyrosine kinase-dependent mechanisms in cultured rat mesangial cells, and the secreted TGF-beta may play a significant role for the stretch-induced expression of extracellular matrix proteins. Our results suggest that stretch-induced TGF-beta of mesangial cells might be a mediator in the progression of glomerular sclerosis as an autocrine/paracrine factor.
肾小球液压升高被认为是肾小球硬化发展的主要致病因素。肾小球压力升高会增加系膜细胞的拉伸程度。因此，本研究旨在探讨机械拉伸对培养的大鼠系膜细胞中转化生长因子-β（TGF-β）和细胞外基质成分表达的影响。结果表明，机械拉伸以时间依赖性方式刺激TGF-β1和TGF-β3的mRNA表达，并且系膜细胞在受到拉伸时会分泌大量的TGF-β蛋白。拉伸还被证明能刺激系膜细胞外基质主要成分I型和IV型胶原蛋白以及纤连蛋白的mRNA表达。针对TGF-β的中和抗体可抑制拉伸诱导的细胞外基质成分的mRNA表达。此外，酪氨酸激酶抑制剂染料木黄酮或赫司特霉素A可抑制拉伸诱导的TGF-β的mRNA表达，而钙通道阻滞剂尼群地平或钆离子（Gd3+）以及蛋白激酶A或C的抑制剂则没有作用。这些发现表明，在培养的大鼠系膜细胞中，拉伸主要通过酪氨酸激酶依赖性机制诱导TGF-β的mRNA表达，并且分泌的TGF-β可能在拉伸诱导的细胞外基质蛋白表达中起重要作用。我们的结果表明，系膜细胞拉伸诱导的TGF-β可能作为自分泌/旁分泌因子在肾小球硬化进展中起介导作用。
