The molecular mechanism of the effect of mechanical stretch on various factors in glomerular cells.

机械牵张对肾小球细胞各因子影响的分子机制。

• 批准号: 10670985
• 负责人: KANAME Shinya
• 金额: $ 2.05万
• 依托单位: The University of Tokyo School of Medicine (Branch Hospital)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670985/
• 关键词: stretch; mesangial cells; TGF-β; LTBP; glomerulosclerosis; glomerular hypertension; extracellular matrix; LOX-1

In glomerular hypertension mesangial cells are believed to perceive the increased cyclic strain and we have recently reported that cyclic mechanical stretch in vitro enhances the expression of ECM components via an autocrine/paracrine secretion of TGF-β in cultured rat mesangial cells. TGF-β is usually secreted as a large latent complex associated with latent TGF-β binding protein-1 (LTBP-1), which is known to bind to extracellular matrix (ECM) components. Because the LTBP-ECM interaction has been suggested to play a role in the activation and biological action of TGF-β, we examined the role of LTBP-1 in the stretch-induced, TGF-β mediated ECM expression. Mesangial cells expressed mRNA for short and long forms of LTBP-1, LTBP-1S and LTBP-1L, respectively. Mesangial cells were subjected to cyclic stretch for 24-36 h in the presence of polyclonal antibody raised against human LTBP-1 or synthetic oligopeptides corresponding to N-terminal portions of human LTBP-1, which is to work as competitive inhibitors against the LTBP-ECM association. Both anti-LTBP-1 antibody and synthetic oligopeptides inhibited the stretch-induced mRNA expression of type I collagen and fibronectin in a dose-dependent manner, but the inhibition by Ab39 and the oligopeptides was recovered by adding recombinant TGF-β Ab39 or the oligopeptides did not change the effect of exogenously added TGF-β such as growth inhibition in mink lung epithelial cells. These results suggest that mesangial cells secrete TGF-β as large latent complex and the LTBP-ECM interaction may be a pivotal step in TGF-β action and ECM accumulation, providing a new therapeutic strategy against progression of glomerulosclerosis and other fibrotic diseases.

在肾小球高血压中，系膜细胞被认为感知到增加的循环应变，我们最近报道体外循环机械拉伸通过培养的大鼠系膜细胞中 TGF-β 的自分泌/旁分泌增强 ECM 成分的表达。 TGF-β 通常作为与潜在 TGF-β 结合蛋白-1 (LTBP-1) 相关的大型潜在复合物分泌，已知该复合物与细胞外基质 (ECM) 成分结合。由于 LTBP-ECM 相互作用已被认为在 TGF-β 的激活和生物作用中发挥作用，因此我们研究了 LTBP-1 在拉伸诱导的 TGF-β 介导的 ECM 表达中的作用。系膜细胞分别表达短形式和长形式的 LTBP-1、LTBP-1S 和 LTBP-1L 的 mRNA。在针对人 LTBP-1 的多克隆抗体或对应于人 LTBP-1 N 端部分的合成寡肽存在下，对系膜细胞进行循环拉伸 24-36 小时，该寡肽将作为针对 LTBP-ECM 关联的竞争性抑制剂。抗LTBP-1抗体和合成寡肽均以剂量依赖性方式抑制拉伸诱导的I型胶原和纤连蛋白的mRNA表达，但通过添加重组TGF-β Ab39可以恢复Ab39和寡肽的抑制作用，或者寡肽不会改变外源添加TGF-β的效果，例如水貂的生长抑制 肺上皮细胞。这些结果表明，系膜细胞分泌 TGF-β 作为大型潜在复合物，LTBP-ECM 相互作用可能是 TGF-β 作用和 ECM 积累的关键步骤，为对抗肾小球硬化症和其他纤维化疾病的进展提供了新的治疗策略。

项目成果

Hori Y., et al.: "Mechanical stretch enhances latent TGF-β binding protein-1 (LTBP-1) expression in cultured rat mesangial cells."Kidney Int.. 53. 1616-1625 (1998)

Hori Y. 等人：“机械拉伸增强培养的大鼠系膜细胞中潜在的 TGF-β 结合蛋白-1 (LTBP-1) 表达。”Kidney Int.. 53. 1616-1625 (1998)

Hori Y.et al.: "Anti-latent TGFβ binding protein-1 antibody or synthetic oligopeptides inhibit extracellular matrix expression induced by ctretch in cultured rat mesangial cells" Kidney Int. 53. 1616-1625 (1998)

Hori Y. 等人：“抗潜伏 TGFβ 结合蛋白 1 抗体或合成寡肽抑制培养的大鼠系膜细胞中 ctretch 诱导的细胞外基质表达”Kidney Int. 53. 1616-1625 (1998)

Hori Y., et al.: "Mechanical stretch enhances latent TGF-β binding protein-1(LTBP-1) expression in cultured rat mesangial cells"Kidney Int.. 53. 1616-1625 (1998)

Hori Y. 等人：“机械拉伸增强培养的大鼠系膜细胞中潜在的 TGF-β 结合蛋白-1 (LTBP-1) 表达”Kidney Int.. 53. 1616-1625 (1998)

Hori Y., et al.: "Mechanical stretch enhances latent TGF-β binding protein-1 (LTBP-1) expression in cultured rat mesangial cells"Kidney Int. 53: 1616-25, 1998.

Hori Y. 等人：“机械拉伸增强培养的大鼠系膜细胞中潜在的 TGF-β 结合蛋白-1 (LTBP-1) 表达”Kidney Int. 53：1616-25，1998。