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诱导心血管损伤分子机制的几个新的生理方面。我们已经证明Aldo直接上调醛固酮诱导的高血压大鼠（Aldo-rats）心血管组织中的ACE。心血管组织中ACE的上调参与了Aldo大鼠局部RAS的激活，这在一定程度上导致了Aldo大鼠心血管组织的氧化应激和炎症改变。我们还表明，在培养的ECs中，Aldo通过矿皮质激素受体（MR）介导的Rac1激活诱导nadph氧化酶依赖性超氧化物的产生。在培养的系膜细胞中，Aldo通过SGK-1介导的NFkB激活增加了ICAM-1和CTGF的表达，并且在Aldo-大鼠肾小球组织中CTGF、ICAM-1和SGK-1的免疫反应性增加。这些结果提示，mr介导的血管细胞内NADPH氧化酶激活与通过ACE上调局部RAS激活构成“恶性循环”，从而导致Aldo诱导的心血管损伤的发生，mr介导的SGK-1-NFkB轴参与了Aldo致肾损伤。

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