Gene therapy by transforming growth factor-β receptor-IgG Fc chimera suppressed extracellular matrix accumulation in experimental glomerulonephritis
Gene therapy by transforming growth factor-β receptor-IgG Fc chimera suppressed extracellular matrix accumulation in experimental glomerulonephritis
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DOI：
10.1046/j.1523-1755.1999.00275.x
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发表时间：
1999-02-01
影响因子：
19.6
通讯作者：
Imai, E
中科院分区：
文献类型：
--
作者：
Isaka, Y;Akagi, Y;Imai, E
背景转化生长因子-β（TGF-β）是纤维化疾病发病机制中的关键介质的证据现在得到几条研究线的支持。这一证据为靶向TGF-β作为抗纤维化药物提供了一定的基础。我们产生了一个嵌合的cDNA，称为TGF β RIL/Fc，编码TGF-β II型受体的细胞外结构域融合到IgG-Fc结构域，并测试TGF β RII/Fc是否可以成为一种新的治疗肾小球疾病的策略。在培养的BNul-7细胞中，重组TGF β RII/Fc逆转了TGF-β 1诱导的抗增殖反应。此外，在培养的正常大鼠肾细胞中，TGF-β RII/Fc减少TGF-β 1诱导的EIIIA阳性纤连蛋白的产生。然后，我们通过日本血凝病毒脂质体介导的基因转移方法将嵌合cDNA导入肾炎大鼠的肌肉中，以便通过嵌合分子的全身递送来阻断肾炎肾小球中的TGF-β活性。TGF β RII/Fc基因转染治疗可抑制肾炎大鼠肾小球TGF-β mRNA的表达，并具有类似的减少细胞外基质积聚的作用。TGF β RII/Fc在体内外均能有效抑制TGF-β的作用，嵌合TGF β RII/Fc基因治疗肾小球硬化症是可行的。
Background. The evidence that transforming growth factor-beta (TGF-beta) is a key mediator in the pathogenesis of fibrotic diseases is now supported by several lines of investigation. This evidence provides a certain base for targeting TGF-beta as an antifibrotic agent.Methods. We generated a chimeric cDNA, termed TGF beta RIL/Fc, encoding an extracellular domain of the TGF-beta type II receptor fused to the IgG-Fc domain, and tested whether TGF beta RII/Fc could be a novel strategy for treating glomerular diseases.Results. In cultured BNul-7 cells, recombinant TGF beta RII/Fc reversed the antiproliferative response induced by TGF-beta 1. In addition, TGF beta RII/Fc diminished the TGF-beta 1-induced production of EIIIA-positive fibronectin in cultured normal rat kidney cells. We then introduced the chimeric cDNA into the muscle of the nephritic rats by the hemagglutinating virus of Japan liposome-mediated gene transfer method in order to block the TGF-beta activity in nephritic glomeruli through systemic delivery of chimeric molecules. Treatment with TGF beta RII/Fc gene transfection could suppress the glomerular TGF-beta mRNA in nephritic rats with a comparable effect in the reduction of extracellular matrix accumulation.Conclusion. TGF beta RII/Fc successfully inhibited the action of TGF-beta in vitro and in vivo, and gene therapy by chimeric TGF beta RII/Fc might be feasible for the therapy of glomerulosclerosis.