Mechanism of aldosterone-induced vascular injury: role of angiotensin II and other factors

醛固酮引起血管损伤的机制：血管紧张素II等因素的作用

• 批准号: 18590804
• 负责人: YOSHIMOTO Takanobu
• 金额: $ 2.48万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590804/
• 关键词: aldosterone; mineralocorticoid receptor; receptor; oxidative stress; renin-angiotensin system; 血管病態学

This study revealed several new physiological aspects of the molecular mechanisms of aldosterone-induced cardiovascular injury. We have demonstrated that Aldo directly upregulates ACE in cardiovascular tissue in aldosterone-induced hypertensive rats (Aldo-rats). ACE upregulation in cardiovascular tissue is involved in the activation of local RAS in Aldo-rats, which partly contributes to oxidative stress and inflammatory changes in cardiovascular tissue of Aldo rats. We have also shown that in cultured ECs Aldo induces of NADPH-oxidase-dependent superoxide generation via mineralocorticoid receptor (MR)-mediated Rac1 activation. In cultured mesagial cell, Aldo increased ICAM-1 and CTGF expression via SGK-1 mediated NFkB activation, and CTGF, ICAM-1, and SGK-1 immunoreactivities were increased in glomerular tissue from Aldo-rats. These results suggest that MR-mediated NADPH oxidase activation in vascular cells and local RAS activation via ACE upregulation compose "vicious cycle", thereby leading to the development of Aldo-induced cardiovascular injury, and that MR-mediated SGK-1-NFkB axis is involved in the renal injury caused by Aldo.

本研究揭示了醛固酮所致心血管损伤分子机制的几个新的生理学方面。我们已经证明，在醛固酮诱导的高血压大鼠(ALDO大鼠)中，ALDO直接上调心血管组织中的ACE。血管紧张素转换酶在心血管组织中的表达上调参与了阿尔多大鼠局部RAS的激活，部分参与了阿尔多大鼠心血管组织的氧化应激和炎症改变。我们还发现，在培养的内皮细胞中，Aldo通过盐皮质激素受体(MR)介导的rac1激活诱导NADPH-氧化酶依赖的超氧化物的产生。在培养的系膜细胞中，Aldo通过SGK-1介导的NFkB活化增加ICAM-1和CTGF的表达，并增加肾小球组织中CTGF、ICAM-1和SGK-1的免疫反应。这些结果提示，MR介导的血管细胞NADPH氧化酶的激活和局部RAS的激活通过ACE的上调构成“恶性循环”，从而导致ALDO所致心血管损伤的发生，MR介导的SGK-1-NFkB轴参与了ALDO所致的肾损伤。

项目成果

Possible involvement of small GTP-binding protein, Rac-1, in aldosterone-stimulated superoxide production in endothelial cells

小 GTP 结合蛋白 Rac-1 可能参与醛固酮刺激的内皮细胞超氧化物产生

• 发表时间: 2007
• 作者: Iwashima F;Yoshimoto T;Sakurada M;Minami I;Hirata Y
• 通讯作者: Hirata Y

「アルドステロンの心血管作用」 原発性アルドステロン症診療マニュアル

《醛固酮对心血管的影响》原发性醛固酮增多症治疗手册

• 发表时间: 2007
• 作者: 吉本貴宣;平田結喜緒
• 通讯作者: 平田結喜緒

Chronic blockade of nitric oxide synthesis reduces adiposity and improves insulin resistance in high fat-induced obese mice

• DOI: 10.1210/en.2006-1371
• 发表时间: 2007-10-01
• 期刊: ENDOCRINOLOGY
• 影响因子: 4.8
• 作者: Tsuchiya, Kyoichiro;Sakai, Haruna;Hirata, Yukio
• 通讯作者: Hirata, Yukio

Endothelial injury and aldosterone.

内皮损伤和醛固酮。

• 发表时间: 2007
• 期刊: Igaku no Ayumi 221
• 作者: Yoshimoto T;Hirata Y.
• 通讯作者: Hirata Y.

心血管リスクホルモンとしてのアルドステロン

醛固酮作为心血管危险激素

• 发表时间: 2006
• 期刊: 細胞 38
• 作者: 吉本貴宣;他
• 通讯作者: 他