The mechanism for activation of aldosterone/mineralocorticoid receptor in life style-related diseases

生活方式相关疾病中醛固酮/盐皮质激素受体的激活机制

• 批准号: 21229012
• 负责人: FUJITA Toshiro
• 金额: $ 135.53万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (S)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009-05-11 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21229012/
• 关键词: アルドステロン; 食塩感受性高血圧; エピジェネティクス; 交感神経; 核内受容体; Rac1; 酸化的ストレス; 鉱質コルチコイド受容体; ポドサイト; 食塩; 生活習慣病; Racl; 心腎連関; 酸化ストレス; 腎障害; メタボリックシンドローム; アルドステロン分泌刺激因子; 肥満糖尿病マウス; 臓器障害

We previously reported the novel mechanism of mineralocorticoid receptor (MR) activation by Rac1 (Nat Med 2008). In this project, we found that activation of Rac1-MR pathway, induced by reactive oxygen species, causes injury of the heart, kidney and brain. Rac1-MR activation in glomerular podocytes and renal tubular cells causes glomerular damage and salt-sensitive hypertension (JCI 2011), respectively.We also found that activation of glucocorticoid receptor (GR), another nuclear receptor, stimulates renal sympathetic activity resulting in activation of GR-WNK4-NCC pathway by changing histone modulation (Nat Med 2011). It suggests that epigenetic modulation is intimately involved in the MR and GR activation with sodium reabsorption in the different tubular sites.Taken together, we identified the two novel pathways of MR- and GR-activation for the development of salt-sensitive hypertension, leading to the clue of epigenetic regulation of organ damage in metabolic syndrome.

我们之前报道了Rac1激活矿皮质激素受体（MR）的新机制（Nat Med 2008）。在本项目中，我们发现活性氧诱导的Rac1-MR通路的激活可引起心脏、肾脏和大脑的损伤。肾小球足细胞和肾小管细胞中的Rac1-MR激活分别导致肾小球损伤和盐敏感性高血压（JCI 2011）。我们还发现，另一种核受体糖皮质激素受体（GR）的激活，通过改变组蛋白调节，刺激肾脏交感神经活动，从而激活GR- wnk4 - ncc通路（Nat Med 2011）。这表明表观遗传调节与不同管状部位的钠重吸收的MR和GR激活密切相关。综上所述，我们确定了MR-和gr -激活两种新的盐敏感性高血压发生途径，从而为代谢综合征器官损伤的表观遗传调控提供了线索。

项目成果

The kidneys and aldosterone/mineralocorticoid receptor system in salt-sensitive hypertension.

盐敏感性高血压中的肾脏和醛固酮/盐皮质激素受体系统。

• DOI: 10.1007/s11906-010-0175-6
• 发表时间: 2011-04
• 期刊: CURRENT HYPERTENSION REPORTS
• 影响因子: 5.6
• 作者: Shibata, Shigeru;Fujita, Toshiro
• 通讯作者: Fujita, Toshiro

Functional characterization of nonsynonymous single nucleotide polymorphisms in the electrogenic Na^+-HCO_3^- cotransporter NBCe1A

产电Na^-HCO_3^-协同转运蛋白NBCe1A中非同义单核苷酸多态性的功能表征

• DOI: 10.1007/s00424-010-0918-x
• 发表时间: 2011
• 期刊: Pflugers Arch
• 作者: Yamazaki O;Yamada H;Suzuki M;Horita S;Shirai A;Nakamura M;Seki G;Fujita T
• 通讯作者: Fujita T

Eplerenone combination Versus conventional Agents to Lower blood pressure on Urinary Antialbuminuric Treatment Effect Study Investigators.Rationale and design of the Eplerenone combination Versus conventional Agents to Lower blood pressure on Urinary Anti

依普利酮组合与传统降血压药物对尿蛋白尿治疗效果研究的研究人员。依普利农组合与传统药物对尿蛋白尿治疗效果降低的基本原理和设计

• 发表时间: 2010
• 期刊: Hypertens Res
• 影响因子: 5.4
• 作者: Ando K;Fujita T;et al.
• 通讯作者: et al.

Mineralocorticoid receptor activation contributes to salt-induced hypertension and renal injury in prepubertal Dahl salt-sensitive rats

• DOI: 10.1093/ndt/gfq197
• 发表时间: 2010-09-01
• 期刊: NEPHROLOGY DIALYSIS TRANSPLANTATION
• 影响因子: 6.1
• 作者: Kawarazaki, Hiroo;Ando, Katsuyuki;Fujita, Toshiro
• 通讯作者: Fujita, Toshiro

Platelet-derived microparticles are removed by a membrane plasma separator.

血小板衍生的微粒通过膜血浆分离器去除。

• 发表时间: 2010
• 期刊: ASAIO J
• 影响因子: 4.2
• 作者: Hanafusa N;Fujita T;et al.
• 通讯作者: et al.