Prevention of acute renal failure by anti-endothelin converting enzyme.

抗内皮素转换酶预防急性肾衰竭。

• 批准号: 09470238
• 负责人: TOMITA Kimio
• 金额: $ 8.26万
• 依托单位: Kumamoto University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470238/
• 关键词: endothelin; receptor antagonist; endothelin converting enzyme-1; acute renal failure; cyclosporine, gene expression; 受容体拮抗薬; エンドセリン交換酵素; 受容体

Endothelin-1 is thought to play a significant role in acute renal failure induced by cyclosporin A.Endothelin converting enzyme-1 (ECE-1) is a key enzyme to produce endothelin. To investigate the role of ECE-1 in the glomerular and tubular dysfunction induced by cyclosporin A, the effects of cyclosporin A on mENA and protein expression of ECE-1, prepro-ET-1, and ETA and ETB type receptor were studied. Prepro-ET-1 rapidly increased in glomeruli 30 to 60 mm. This rapid increase was followed byan increase in plasma ET-1 levels. These increases were followed by decreased expression of ECE- 1, ETA and ETB type receptor mRNA It is suggested that downregulation of glomerular and tubular ECE-1 expression may be one of defense mechanisms of ET system in acute renal failure induced by cyclosporin A.This downregulation may be caused by increased ET-1 or cyclosporin A itself. To investigate the precise mechanism of downregulation of ECE-1 mRNA, the effects of ET-1 was studied in cultured endothelial cells. Incubation of ETA for 6 hours caused a significant decrease in ECE-1 mRNA expression. This effect was was abolished by co-incubation with BQ788, a specific ETB receptor antagonist , but not by co-incubation with BQ123, a specific ETA receptor antagonist. These results suggested that ET-1 suppressed ECE-1 expression through ETB receptor, indicating the existence of a feedback mechanism of FT-1 on ECE-1 in endothelial cells.

Endothelin-1被认为在环孢素A诱导的急性肾功能衰竭中发挥着重要作用。内皮素转换酶-1（ECE-1）是产生内皮素的关键酶。为了探讨ECE-1在环孢菌素A诱导的肾小球和肾小管功能障碍中的作用，研究了环孢菌素A对mENA以及ECE-1、prepro-ET-1、ETA和ETB型受体蛋白表达的影响。 Prepro-ET-1 在肾小球 30 至 60 mm 中迅速增加。这种快速增加之后血浆 ET-1 水平也随之增加。 ECE-1、ETA、ETB型受体mRNA表达量增加后，肾小球和肾小管ECE-1表达下调可能是环孢素A诱导的急性肾功能衰竭ET系统的防御机制之一。这种下调可能是由ET-1或环孢素A本身增加引起的。为了研究 ECE-1 mRNA 下调的精确机制，在培养的内皮细胞中研究了 ET-1 的作用。 ETA 孵育 6 小时导致 ECE-1 mRNA 表达显着降低。与特异性 ETB 受体拮抗剂 BQ788 共孵育可消除该效应，但与特异性 ETA 受体拮抗剂 BQ123 共孵育则不会消除该效应。这些结果表明，ET-1通过ETB受体抑制ECE-1的表达，表明内皮细胞中FT-1对ECE-1的反馈机制的存在。

项目成果

Nakayama Yushi,: "Endothelin-1 inhibits endothelin converting enzyme-1 expression in cultured rat pulmonary endothelial cells." Circulation. 97. 234-236 (1998)

Nakayama Yushi，：“内皮素-1 抑制培养的大鼠肺内皮细胞中内皮素转换酶-1 的表达。”

Naomi, S., T.Iwaoka, T.Disashi, J.Inoue, Y.Kanesaka, H.Tokunaga, K.Tomita.: "Endothelin -1 inhibits endothelin converting enzyme-1 expression in cultured rat pulmonary endothelial cells." Circulation. 97. 234-236 (1998)

Naomi, S.、T.Iwaoka、T.Disashi、J.Inoue、Y.Kanesaka、H.Tokunaga、K.Tomita.：“内皮素 -1 抑制培养的大鼠肺内皮细胞中内皮素转换酶 1 的表达。”

Y. Kitamoto,: "Vascular endothelial growth factor (VEGF) is an essential molecule for mouse kidney development : glomerulogenesis and nephrogenesis." J. Clin. Invest.,. 99. 2351-2357 (1997)

Y. Kitamoto：“血管内皮生长因子 (VEGF) 是小鼠肾脏发育的重要分子：肾小球发生和肾发生。”

Kitamoto Y.: "Vascular endothelial growth factor(VEGF)is an essential molecule for mouse kidney development: glomerulogenesis and nephrogenesis." J.Clin.Invest.99. 2351-2357 (1997)

Kitamoto Y.：“血管内皮生长因子（VEGF）是小鼠肾脏发育的重要分子：肾小球发生和肾发生。”

Nakayama Yushi,: "Intranephron distribution and regulation of endothelin converting enzyme - 1 in cycloporine A - induced acute renal failure in rats." J.Am.Soc.Nephrol.(in press). (1998)

Nakayama Yushi，“环孔素 A 中内皮素转换酶 - 1 的肾内分布和调节 - 诱导大鼠急性肾衰竭。”