REGULATION OF TGF-β ACTIVITY FOR ATTENUATION OF GLOMERULAR LESIONS

调节 TGF-β 活性以减轻肾小球病变

• 批准号: 10470219
• 负责人: OKUDA Seiya
• 金额: $ 4.03万
• 依托单位: KURUME UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 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-10470219/
• 关键词: Growth factor; TGF-β; Soluble receptor; Glomerulosclerosis; Renal fibrosis; matrix; TGF-β activation

The extracellular domain of TGF-β type 2 receptor can bind active TGF-β tightly but does not involve signal transduction of TGF-β. Therefore, a large amount of TGF-β soluble receptor can prevent TGF-β binding to true TGF-β receptor. To investigate the effects of TGF-β soluble receptor on TGF-β action in vivo, the gene of TGF-β type 2 receptor extracellular domain was transfected into the muscle of rats by using 5x10ィイD18ィエD1 recombinant adenovirus vector at 1 days before the unilateral uretal obstruction. Serum concentration of TGF-β soluble receptor was quantitated by ELISA assay. The serum concentration of the soluble receptor at 10 days after the transfection was 70ng/ml, which was 50-fold higher than reported concentration of active form TGF-β in rats serum and considered to be sufficient to block the active TGF-β in vivo. Tubular damage and interstitial fibrosis were marked in ureteral obstruction rat kidney. These lesions were attenuated by the elevated level of the TGF-β soluble receptor. Interstitial fibronectin accumulation, vimentin expression and macrophage accumulation were markedly decreased by TGF-β soluble receptor gene transfection. TGF-β type 2 soluble receptor is a potent inhibitor of TGF-βto modulate renal fibrosis.

转化生长因子-β2型受体胞外区可与活性转化生长因子-β紧密结合，但不参与转化生长因子-β的信号转导。因此，大量的转化生长因子-β可溶性受体可以阻止转化生长因子-β与真正的转化生长因子-β受体结合。为探讨转化生长因子-β可溶性受体在体内对转化生长因子-β作用的影响，在单侧输尿管梗阻前1d，用5×10-ィイD18-ィエ-D_1重组腺病毒载体将转化生长因子-RNA 2型受体胞外区基因导入大鼠肌肉。用双抗体夹心ELISA法测定血清转化生长因子-β可溶性受体浓度。转染后第10天血清中可溶性受体浓度为70 ng/ml，是报道的大鼠血清中活性形式转化生长因子-β浓度的50倍，被认为足以在体内阻断活性转化生长因子-β。输尿管梗阻大鼠肾小管损伤和间质纤维化明显。这些损伤通过转化生长因子-β可溶性受体水平的升高而减轻。转化生长因子-β可溶性受体基因转染组间质纤维连接蛋白积聚、波形蛋白表达和巨噬细胞积聚明显减少。转化生长因子-β2型可溶性受体是转化生长因子-β调节肾纤维化的有效抑制剂。

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