REGULATION OF TGF-β AND ITS SIGNAL MOLECULE, SMAD, FOR ATTENUATION OF GLOEMRULAR DISEASE.

调节 TGF-β 及其信号分子 SMAD，以减轻肾小球疾病。

• 批准号: 11671063
• 负责人: TAMAKI Kiyoshi
• 金额: $ 2.3万
• 依托单位: KURUME UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671063/
• 关键词: Growth factor; TGF-β; Smad; glomerulonephritis; glomerulosclerosis; renal fibrosis; Adenovirus-vector; TGF-β; アンギオテンシンII; IgA腎症; アデノウイルス; 活性化; ステロイド; メザンギウム細胞; マトリックス蛋白; PAI-1; 遺伝子導入

TGF-β1 plays a pathological role in fibrotic diseases including glomerulosclerosis and renal fibrosis. Smads have been identified as pivotal components in TGF-β intracellular signaling. The present study was carried out to investigate TGF-β1-induced Smad activation in cultured mesangial cells and experimental mesangioproliferative glomerulonephritis in rats. In mesangial cells, TGF-β1, but not BMP-7, induced phosphorylation of Smad2. In contrast, BMP-7, but not TGF-β1, induced phosphorylation of BMP-related Smads. TGF-β1 stimulated the phosphorylation of Smad2 in a dose- and time-dependent manner. Gene transfer using Adenovirus-vector, double-overexpression of Smad2 and Smad4 induced TGF-β1-stimulated plasminogen activator inhibitor-1 (PAI-1) expression more than overexpression of each Smad alone. Furthermore, overexpression of Smad7, one of inhibitory Smads, but not Smd6, blocked TGF-β1-induced PAI-1 expression and reversed TGF-β1-inhibited cell proliferation by inhibiting Smad2 phosphorylation. In experimental glomerulonephritis using Thy-1 nephritis, Smad2 phosphorylation increased transiently and significantly in a similar manner to glomerular matrix expansion. Phosphorylated Smad2 was observed in the damaged glomeruli. These results suggested that Smad proteins are present and act as signaling molecule of TGF-β in mesangial cells in vitro and in vivo. Our results indicate the possibility that modulation of Smad activity may attenuate the development of glomerulosclerosis and fibrosis

转化生长因子-β-1在肾小球硬化、肾纤维化等纤维化疾病中起病理作用。Smads被认为是转化生长因子-β细胞内信号转导的关键成分。本研究旨在探讨转化生长因子-β-1对大鼠系膜细胞和实验性系膜增生性肾炎肾小球系膜细胞Smad1激活的影响。在系膜细胞中，转化生长因子-骨形态发生蛋白-β1，而不是骨形态发生蛋白-7诱导Smad2的磷酸化。相反，骨形态发生蛋白-7，而不是转化生长因子-β1，诱导了骨形态发生蛋白相关的Smads的磷酸化。转化生长因子-β-1以剂量和时间依赖的方式刺激Smad2的磷酸化。用腺病毒载体进行基因转移，Smad2和Smad4的双过表达诱导转化生长因子-β-1刺激的纤溶酶原激活物抑制物-1的表达高于单独过表达各自的Smad1。此外，Smad7的过表达可阻断转化生长因子-β1诱导的PAI-1的表达，并逆转转化生长因子-β1通过抑制Smad2的磷酸化而抑制细胞增殖。在Thy-1肾炎的实验性肾小球肾炎中，Smad2的磷酸化以类似于肾小球基质扩张的方式短暂而显著地增加。损伤肾小球内可见磷酸化的Smad2。这些结果表明，Smad蛋白在体外和体内均存在于系膜细胞中，并作为转化生长因子-β的信号分子。我们的结果表明，Smad活性的调节可能会减缓肾小球硬化和纤维化的发展。

项目成果

Kashiwagi M,Tamaki K et al: "Locally activated renin-angiotensin system associated with TGF-beta1 as a major factor for renal injury induced by chronic inhibition of nitric oxide synthase in rats."J Am Soc Nephrology. 11. 616-624. (2000)

Kashiwagi M、Tamaki K 等人：“局部激活的肾素-血管紧张素系统与 TGF-β1 相关，是大鼠慢性抑制一氧化氮合酶诱导肾损伤的主要因素。”J Am Soc Nephrology。

Ishisaki A,Tamaki, et al: "Differential inhibition of Smad6 and Smad7 on bone morphogenetic protein- and activin-mediated growth arrest and apoptosis in B cells"J Biol Chem. 274. 13637-13642 (1999)

Ishisaki A、Tamaki 等人：“Smad6 和 Smad7 对 B 细胞中骨形态发生蛋白和激活素介导的生长停滞和凋亡的差异抑制”J Biol Chem。

Tamai O, Tamaki K,, Okuda S et al: "Caveolae in mesangial cells and caveolin expression in mesangial proliferative glomerulonephritis."Kidney Int.. 59. 471-480 (2001)

Tamai O、Tamaki K、Okuda S 等人：“系膜细胞中的小窝和小窝蛋白在系膜增殖性肾小球肾炎中的表达。”Kidney Int.. 59. 471-480 (2001)

Tamaki K: "Transforming Growth Factor(TGF)-β1 Induced Phosphorylation of Smad2 in Mesangial Cells In Vitro and In Vivo."J Am Soc Nephrol. 10巻. 581 (1999)

Tamaki K：“转化生长因子 (TGF)-β1 在体外和体内诱导系膜细胞磷酸化。J Am Soc Nephrol。”

Tamaki K,Okuda S et al: "Transforming growth factor-β1 induced phosphorylation of Smad2 in mesangial cells in vitro and in vivo."J Am Soc Nephrology.. 10. 581-581 (1999)

Tamaki K、Okuda S 等人：“转化生长因子-β1 在体外和体内诱导系膜细胞中 Smad2 的磷酸化。”J Am Soc Nephrology.. 10. 581-581 (1999)