Regulation of SLCO4C1 transporter-mediated excretion of uremic toxins as a therapeutic strategy for Chronic Kidney Disease

调节 SLCO4C1 转运蛋白介导的尿毒症毒素排泄作为慢性肾病的治疗策略

• 批准号: 24890013
• 负责人: AKIYAMA Yasutoshi
• 金额: $ 1.91万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Research Activity Start-up
• 财政年份: 2012
• 资助国家: 日本
• 起止时间: 2012-08-31 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-24890013/
• 关键词: トランスポーター; 尿毒症; 尿毒素; 慢性腎臓病; SLCO4C1; インドキシル硫酸; 尿毒症物質

Chronic kidney disease (CKD) is a global health problem that carries a substantial risk for cardiovascular morbidity and death. With the progression of CKD, various uremic toxins accumulate, subsequently causing renal damage and hypertension. Recently, we have revealed that kidney-specific organic anion transporter SLCO4C1 excretes uremic toxins, and the up-regulation of SLCO4C1 resulted in the reduction of blood pressure and renal inflammation in a CKD model. In this study, we revealed that indoxyl sulfate (IS), one of the best-known uremic toxins, inhibits the expression of SLCO4C1 through GATA3 and that removal of IS increases the SLCO4C1 expression. The combination therapy of, (1) activating the SLCO4C1 expression by statins, (2) reducing the plasma IS concentration by the administration of AST-120 and (3) administering GATA inhibitor, could be a more effective remedy for the excretion of uremic toxins and preservation of renal function in CKD patients.

慢性肾脏疾病(CKD)是一个全球性的健康问题，对心血管疾病的发病率和死亡率具有很大的风险。随着CKD的进展，各种尿毒症毒素积聚，继而导致肾脏损害和高血压。最近，我们发现肾脏特异的有机阴离子转运体SLCO4C1分泌尿毒症毒素，在CKD模型中，SLCO4C1的上调导致血压降低和肾脏炎症。在本研究中，我们揭示了最著名的尿毒症毒素之一吲哚硫酸盐(IS)通过GATA3抑制SLCO4C1的表达，而去除IS会增加SLCO4C1的表达。(1)他汀类药物激活SLCO4C_1表达，(2)应用AST-120降低血浆IS浓度，(3)应用GATA抑制剂联合治疗，可能是一种更有效的治疗CKD患者尿毒症毒素排泄和保护肾功能的方法。

项目成果

Annual Review腎臓

年度回顾肾脏

• 发表时间: 2008
• 作者: Matsuzawa A.;et. al.;伊藤恭典
• 通讯作者: 伊藤恭典

尿毒素の輸送とCKD

尿液毒素转运和 CKD

• 发表时间: 2013
• 期刊: 腎と骨代謝
• 作者: 2.秋山泰利;阿部高明
• 通讯作者: 阿部高明

A metabolomic approach to clarifying the effect of AST-120 on 5/6 nephrectomized rats by capillary electrophoresis with mass spectrometry (CE-MS).

• DOI: 10.3390/toxins4111309
• 发表时间: 2012-11-14
• 期刊: Toxins
• 影响因子: 4.2
• 作者: Akiyama Y;Takeuchi Y;Kikuchi K;Mishima E;Yamamoto Y;Suzuki C;Toyohara T;Suzuki T;Hozawa A;Ito S;Soga T;Abe T
• 通讯作者: Abe T

Indole-3-acetate Inhibits Erythropoietin Receptor Expression and Erythropoietin Signaling in vitro

Indole-3-acetate 在体外抑制促红细胞生成素受体表达和促红细胞生成素信号传导

• 发表时间: 2013
• 作者: Kaneko H;Kobayashi E;Yamamoto M;Shimizu R;間石奈湖;秋山 泰利
• 通讯作者: 秋山 泰利

Metabolomic approach for clarifying the effect of AST-120 in 5/6 nephrectomized rats by capillary electrophoresis mass spectrometry

通过毛细管电泳质谱法阐明 AST-120 对 5/6 肾切除大鼠的影响的代谢组学方法

• 发表时间: 2012
• 作者: Nomura T;Bando Y;Bochimoto H;Koga D;Watanabe T;Yoshida S.;秋山 泰利
• 通讯作者: 秋山 泰利