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.

TGF-β2型受体的细胞外域可以紧密结合活性TGF-β，但不涉及TGF-β的信号转导。因此，大量的TGF-β固体受体可以防止TGF-β与真正的TGF-β受体结合。为了研究TGF-β固体受体对体内TGF-β作用的影响，通过使用5x10 D18 D18 D1重组腺病毒载体在单一产量输尿管对象构造之前，将TGF-β2型受体外细胞外域的基因转化为大鼠的大鼠肌肉。通过ELISA分析对TGF-β固体受体的血清浓度进行定量。转化后10天，固体受体的血清浓度为70ng/mL，比报道的大鼠血清中活性形式TGF-β的浓度高50倍，被认为足以阻止活性TGF-β在体内。管状损伤和间质纤维化在输尿管异议大鼠肾脏中标记。这些病变被TGF-β可溶受体的升高水平减弱。 TGF-β可溶性受体基因转染明显降低间质纤连蛋白丙烯酸表达和巨噬细胞丙烯酸。 TGF-β2型可溶性受体是TGF-β的潜在抑制剂，以调节肾纤维化。

项目成果

Usui M, Matsuoka H, Miyazaki H et al.: "Increased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure."Life Science. 62. 2425-2430 (1998)

Usui M、Matsuoka H、Miyazaki H 等人：“充血性心力衰竭患者内源性一氧化氮合酶抑制剂增加。”生命科学。

Ueda S: "Tetrahydrobiopterin restores endothelial function in chronic smokers"J Am Coll Cardiol. 35. 71-75 (2000)

Ueda S：“四氢生物蝶呤可恢复慢性吸烟者的内皮功能”J Am Coll Cardiol。

Miyazaki H, Matsuoka H, Usui M et al.: "Endogenous nitric oxide sythase inhibitor, a novel marker of atherosclerosis."Circulation. 99. 1141-1146 (1999)

Miyazaki H、Matsuoka H、Usui M 等人：“内源性一氧化氮合酶抑制剂，动脉粥样硬化的新标志物。”循环。

Higashi H, Okuda S, Tamaki K et al.: "The effects of a high salt diet on gene expression of Na+/H+ exchanger and growth in 5/6-nephrectomized rats."Nephrology. 4. 187-193 (1998)

Higashi H、Okuda S、Tamaki K 等人：“高盐饮食对 Na /H 交换器基因表达和 5/6 肾切除大鼠生长的影响。”肾脏病学。

Ishibashi M, Nishida H, Okuda S et al.: "Localization of parathyroid glands in hemodialysis patients using Tc-99m sestamibi imaging.."Nephron. 78. 48-53 (1998)

Ishibashi M、Nishida H、Okuda S 等人：“使用 Tc-99m sestamibi 成像对血液透析患者的甲状旁腺进行定位。”肾单位。