Targeting oxidative stress and new therapy in metabolic syndrome

针对代谢综合征的氧化应激和新疗法

• 批准号: 17209034
• 负责人: FUJITA Toshiro
• 金额: $ 30.78万
• 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 (A)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17209034/
• 关键词: Oxidative stress; Organ regeneration; Metabolic syndrome; aldosterone; inflammation; salt; adrenomedullin; 遺伝子変異; 脂肪細胞; 腎障害

In the present study, we have investigated new therapeutic approaches to metabolic syndrome. We have focused on the role of salt, aldosterone, inflammation, and adrenomedullin in relation to oxidative stress and seek new targets to reduce oxidative stress and thus protect organs from damages. In addition, we investigated possible therapeutic approaches to induce organ regenerations and new genes in metabolic model rats. We revealed that orally loaded salt increases ROS and aggravates insulin resistance, and cardiac function. Adrenomedullin has been reported as an intrinsic antioxidants and its deficiency induces metabolic syndrome. Mac-1 is expressed on leukocyte and plays an important role in leukocyte adherence and vascular damages. Using Local Shwartzman Reaction model, we revealed role of Mac-1 in vasculitis and possible therapeutic target in preventing vascular damages in metabolic syndrome where local vascular inflammation could be one pathogenesis. To induce organ regeneration i … More s a promising therapeutic tool and in renal damages, we focused on side population cell as a multipotent stem cells in the kidney. Using several renal impairment models, we revealed that cytokines induce side population cell apoptosis and suppresses organ regeneration. Aldosterone blockade, angiotensin II blockade as well as epigenetical regulation by trichostatin A could rescue side population cells in damaged kidney. Finally we investigated possible genetical locus in metabolic syndrome model rat and found responsible locus on chromosome 3, 4 and 12. Among them, mutation in kynurenine aminotransferase-1 links body weight, blood pressure, NEFA synthesis and insulin resistance in rat model. In conclusion, the present research project revealed several new insights in therapeutic target in metabolic syndrome. The importance of oxidative stress and aldosterone as well as epigenetical regulations and new gene are all play pivotal role in pathogenesis of metabolic syndrome and related organ damages. There are several possible compounds are now available that lead us to a new era in treating metabolic syndrome. Less

在本研究中，我们研究了代谢综合征的新治疗方法。我们重点研究了盐、醛固酮、炎症和肾上腺髓质素在氧化应激中的作用，并寻找新的靶点来减少氧化应激，从而保护器官免受损害。此外，我们还研究了诱导新陈代谢模型大鼠器官再生和新基因的可能治疗方法。我们发现，口服盐增加了ROS，加重了胰岛素抵抗和心功能。肾上腺髓质素是一种内源性抗氧化剂，缺乏肾上腺髓质素会导致代谢综合征。Mac-1表达于白细胞上，在白细胞黏附和血管损伤中发挥重要作用。利用局部Shwartzman反应模型，我们揭示了Mac-1在血管炎中的作用，以及可能的治疗靶点，以防止代谢综合征的血管损伤，局部血管炎症可能是一个发病机制。诱导器官再生--I…S更是一个很有前途的治疗工具，在肾脏损害方面，我们重点研究了侧群细胞作为一种多能干细胞在肾脏中的作用。使用几种肾脏损伤模型，我们发现细胞因子诱导副细胞凋亡并抑制器官再生。醛固酮阻断、血管紧张素II阻断以及曲古抑素A的表观遗传调节可挽救受损肾脏的侧群细胞。最后，我们对代谢综合征模型大鼠可能的遗传位点进行了研究，发现了位于第3、4和12号染色体上的可能的遗传位点。其中，犬尿氨酸转氨酶-1突变与体重、血压、NEFA合成和胰岛素抵抗有关。总之，本研究项目在代谢综合征的治疗靶点方面揭示了几个新的见解。氧化应激和醛固酮的重要性以及表观遗传调控和新基因在代谢综合征及其相关器官损害的发病机制中起着关键作用。现在有几种可能的化合物将我们带入治疗代谢综合征的新纪元。较少

项目成果

Sympatho-inhibitory action of endogenous adrenomedullin through inhibition of oxidative stress in the brain

• DOI: 10.1161/01.hyp.0000165690.85505.37
• 发表时间: 2005-06-01
• 期刊: HYPERTENSION
• 影响因子: 8.3
• 作者: Fujita, M;Kuwaki, T;Fujita, T
• 通讯作者: Fujita, T

Adrenomedullin inhibits angiotensin II-induced oxidative stress via Csk-mediated inhibition of Src activity.

• DOI: 10.1152/ajpheart.00486.2006
• 发表时间: 2007-04
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Jing Liu;T. Shimosawa;Hiromitsu Matsui;F. Meng;S. Supowit;D. DiPette;K. Ando;T. Fujita

Adrenomedullin inhibits insulin exocytosis via pertussis toxin-sensitive G-protein-coupled mechanism.

肾上腺髓质素通过百日咳毒素敏感的 G 蛋白偶联机制抑制胰岛素胞吐作用。

• 发表时间: 2006
• 期刊: Am J Physiol 291
• 作者: Sekine N;Takano K;Kimata-Hayashi N;Kadowaki T;Fujita T
• 通讯作者: Fujita T

Inhibition of histone deacetylase activates side population cells in kidney and partially reverses chronic renal injury

• DOI: 10.1634/stemcells.2007-0049
• 发表时间: 2007-01-01
• 期刊: STEM CELLS
• 影响因子: 5.2
• 作者: Imai, Naohiko;Hishikawa, Keiichi;Fujita, Toshiro
• 通讯作者: Fujita, Toshiro

Paradoxical mineralocorticoid receptor activation and left ventricular diastolic dysfunction under high oxidative stress conditions

• DOI: 10.1097/hjh.0b013e328300a232
• 发表时间: 2008-07
• 期刊: Journal of Hypertension
• 影响因子: 4.9
• 作者: Hong Wang;T. Shimosawa;Hiromitsu Matsui;Tomoyo Kaneko;S. Ogura;Y. Uetake;K. Takenaka;Y. Yatomi;T. Fujita