Pathophysiological mechanisms and therapeutic targets in multiple organ damages in metabolic syndrome

• Project/Area Number: 20591048
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: The University of Tokyo
• Principal Investigator: SHIMOSAWA Tatsuo The University of Tokyo, 医学部附属病院, 講師 (90231365)
• Co-Investigator(Renkei-kenkyūsha): IKEDA Hitoshi 東京大学, 医学部附属病院, 准教授 (80202422) ; ANDO Katsuyuki 東京大学, 医学部附属病院, 准教授 (60184313)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2010: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2009: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2008: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: レニンアンジオテンシン / 肝障害 / 血管障害 / 酸化ストレス / メタボリックシンドローム / アンジオテンシン / 炎症 / 星細胞 / 食塩感受性

Research Abstract

Oxidized LDL receptor (LOX-1) further increased oxidative stress that was induced by dietary manipulations. Under this condition, liver developed fatty liver with fibrosis which resembles NASH in human and atherosclerosis developed in the kidney and aorta. Renin inhibitor or antioxidants reversed changes in the liver. It was suggested that local renin-angiotensin system in the liver may be an intermediate in the vicious cycle of oxidative stress and LOX-1. And targeting renin-angiotensin system may be a possible therapeutic target in metabolic syndrome.

Research Products

• [Journal Article] Epigenetic modulation of the renal ・-adrenergic-WNK4 pathway in salt-sensitive hypertension. (2011)
  • Author(s): Mu S.Y., Shimosawa T, Ogura S., Wang H., Uetake Y., Kawakami-Mori F., Marumo T., Yatomi Y., Geller D.S., Tanaka H., Fujita T.
  • Journal Title: Nat Med 17 Pages: 573-80
  • Peer Reviewed
• [Journal Article] Protective effects of statin on cardiac fibrosis and apoptosis in adrenomedullin-knockout mice treated with angiotensin II and high salt loading. (2011)
  • Author(s): Yamamoto C, Fukuda N, Jumabay M, Saito K, Matsumoto T, Ueno T, Soma M, Matsumoto K, Shimosawa T.
  • Journal Title: Hypertens Res 34 Pages: 348-353
  • Peer Reviewed
• [Journal Article] Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension (2011)
  • Author(s): Mu, S.Y., Shimosawa, T, Ogura, S., Wang, H., Uetake, Y., Kawakami-Mori, F., Marumo, T., Yatomi, Y., Geller, D.S., Tanaka, H., Fujita, T.
  • Journal Title: Nature Medicine Volume: (In press)(掲載確定)
  • Peer Reviewed
• [Journal Article] Effects of adrenoemdullin on nitric oxide production during forebrain ischemia and reperfusion in mice. (2010)
  • Author(s): Kato Y., Araki N., Ohkubo T., Asano Y., Furuya D., Hattori K., Simazu T., Yamazato M., Nagoya H., Ito Y., Shimosawa T., Fujita T., Shimazu K.
  • Journal Title: Cerebral Blood Flow and Metabolism 21 Pages: 1-6
  • Peer Reviewed
• [Journal Article] Restraint stress induces coneexin-43 translocation via ・-adrenoceptors in rat heart. (2010)
  • Author(s): Unuma K., Shintani-Ishida K., Yahagi N., Tsushima K., Shimosawa T., Ueyama T., Yoshida K.
  • Journal Title: Circ J 74 Pages: 2693-2701
  • Peer Reviewed
• [Journal Article] Connexin-43 Redistribution and Gap Junction Activation During Forced Restraint Protects Against Sudden Arrhythmic Death in Rats. (2010)
  • Author(s): Unuma K., Shintani-Ishida K., Tsushima K., Shimosawa T., Ueyama T., Kuwahara M., Yoshida K.
  • Journal Title: Circ J 74 Pages: 1087-1095
  • Peer Reviewed
• [Journal Article] Protective effects of statin on cardiac fibrosis and apoptosis in adrenomedullin-knockout mice treated with angiotensin II and high salt loading. (2010)
  • Author(s): Yamamoto C, Fukuda N, Jumabay M, Saito K, Matsumoto T, Ueno T, Soma M, Matsumoto K, Shimosawa T.
  • Journal Title: Hypertens Res Volume: 34 Pages: 348-353
  • Peer Reviewed
• [Journal Article] Effects of adrenoemdullin on nitric oxide production during forebrain ischemia and reperfusion in mice. (2010)
  • Author(s): Kato, Y., Araki, N., Ohkubo, T., Asano, Y., Furuya, D., Hattori, K., Simazu, T., Yamazato, M., Nagoya, H., Ito, Y., Shimosawa, T., Fujita, T., Shimazu, K
  • Journal Title: Cerebral Blood Flow and Metabolism Volume: 21 Pages: 1-6
  • Peer Reviewed
• [Journal Article] Restraint stress induces coneexin-43 translocation via a-adrenoceptors in rat heart. (2010)
  • Author(s): Unuma, K., Shintani-Ishida, K., Yahagi, N., Tsushima, K., Shimosawa T., Ueyama, T., Yoshida, K.
  • Journal Title: Circ J Volume: 74 Pages: 2693-2701
  • Peer Reviewed
• [Journal Article] Connexin-43 Redistribution and Gap Junction Activation During Forced Restraint Protects Against Sudden Arrhythmic Death in Rats. (2010)
  • Author(s): Unuma, K., Shintani-Ishida, K., Tsushima, K., Shimosawa, T., Ueyama, T., Kuwahara, M., Yoshida, K
  • Journal Title: Circ J Volume: 74 Pages: 1087-1095
  • Peer Reviewed
• [Journal Article] Mac-1 (CD11b/CD18) links inflammation and thrombosis after glomerular injury. (2009)
  • Author(s): Hirahashi J., Hishikawa K., Kaname S., Tsuboi N., Wang Y., Simon D.I., Stavrakis G., Shimosawa T., Xiao L., Nagahama Y., Suzuki K., Fujita T., Mayadas T.N.
  • Journal Title: Circulation. 120 Pages: 1255-1265
  • Peer Reviewed
• [Journal Article] PKA-dependent suppression of ROS in transient focal ischemia in adrenomedullin-deficient mice. (2009)
  • Author(s): Miyamoto N., Tanaka R., Shimosawa T., Yatomi Y., Fujita T., Hattori N., Urabe T.
  • Journal Title: J Cereb Blood Flow Metab. 29 Pages: 1769-1779
  • Peer Reviewed
• [Journal Article] Sphingosine 1-phosphate regulates regeneration and fibrosis after liver injury via sphingosine 1-phosphate receptor 2. (2009)
  • Author(s): Ikeda H., Watanabe N., Ishii I., Shimosawa T., Kume Y., Tomiya T., Inoue Y., Nishikawa T., Ohtomo N., Tanoue Y., Iitsuka S., Fujita R., Omata M., Chun J., Yatomi Y.
  • Journal Title: J.Lipid Res. 50 Pages: 556-564
  • Peer Reviewed
• [Journal Article] Fasting-Induced hypothermia and reduced energy production in mice lacking acetyl-CoA synthetase 2. (2009)
  • Author(s): Sakakibara I., Fujino T., Ishii M., Tanaka T., Shimosawa T., Miura S., Zhang W., Tokutake Y., Yamamoto J., Awano M., Iwasaki S., Motoike T., Okamura, M., Inagaki T., Kita K., Ezaki O., Naito M., Kuwaki T., Chohnan S., Yamamoto T.T., Hammer R.E., Kodama T., Yanagisawa M., Sakai J.
  • Journal Title: Cell Metabolism 9 Pages: 191-202
  • Peer Reviewed
• [Journal Article] Connexin-43 Redistribution and Gap Junction Activation During Forced Restraint Protects Against Sudden Arrhythmic Death in Rats. (2009)
  • Author(s): Unuma, K., Shintani-Ishida, K., Tsushima, K., Shimosawa, T., Ueyama, T., Kuwahara, M., Yoshida, K.
  • Journal Title: Circ J (In press)
  • Peer Reviewed
• [Journal Article] Fasting-Induced hypothermia and reduced energy production in mice lacking acetyl-CoA synthetase 2 (2009)
  • Author(s): Sakakibara, I., Fujino, I., Ishii, M., Tanaka, T., Shimosawa, T., Miura, S., Zhang, W., Tokutake, Y., Yamamoto, J., Awano, M., Iwasaki, S., Motoike, T., Okamura, M., Inagaki, T., Kita, K., Ezaki, O., Naito, M., Kuwaki, T., Chohnan, S., Yamamoto, T.T., Hammer, R.E.Kodama, T., Yanagisawa, M., Sakai, J
  • Journal Title: Cell Metabolism 9 Pages: 191-202
  • Peer Reviewed
• [Journal Article] Mac-1(CD11b/CD18)links inflammation and thrombosis after glomerular injury. (2009)
  • Author(s): Hirahashi, J., Hishikawa, K., Kaname, S., Tsuboi, N., Wang, Y., Simon, D.I., Stavrakis, G., Shimosawa T., Xiao, L., Nagahama, Y., Suzuki, K., Fujita, T., Mayadas, T.N.
  • Journal Title: Circulation 120 Pages: 1255-1265
  • Peer Reviewed
• [Journal Article] Sphingosine 1-phosphate regulates regeneration and fibrosis after liver injury via sphingosine 1-phosphate receptor 2. (2009)
  • Author(s): Ikeda, H., Watanabe, N., Ishii, I., Shimosawa.T., Kume, Y., Tomiya, T., Inoue, Y., Nishikawa, T., Ohtomo, N., Tanoue, Y., Iitsuka, S., Fujita, R., Omata, M., Chun, J., Yatomi, Y.
  • Journal Title: J.Lipid Res. 50 Pages: 556-564
  • Peer Reviewed
• [Journal Article] PKA-dependent suppression of ROS in transient focal ischemia in adrenomedull in-deficient mice. (2009)
  • Author(s): Miyamoto, N., Tanaka, R., Shimosawa.T., Yatomi, Y., Fujita, T., Hattori, N., Urabe, T.
  • Journal Title: J Cereb Blood Flow Metab. 29 Pages: 1769-1779
  • Peer Reviewed
• [Journal Article] Fasting-Induced hypothermia and reduced energy production in mice lacking acety 1-CoA synthetase 2 (2009)
  • Author(s): Sakakibara, I., Fujino, T., Ishii, M., Tanaka, T., Shimosawa, T., Miura, S., Zhang, W., Tokutake, Y., Yamamoto, J., Awano, M., Iwasaki, S Motoike, T., Okanaura, M., Inagaki, T., Kita, K., Ezaki, 0., Naito, M., Kuwaki, T., Chohnan, S., Yama moto, T.T., Hammer, R.E., Kodanta, T., Yanagisawa, M., and Sakai, J
  • Journal Title: Cell Metabolism 9 Pages: 191-202
  • Peer Reviewed
• [Journal Article] Salt excess causes left ventricular diastolic dysfunction in rats with metabolic disorder. (2008)
  • Author(s): Matsui H, Ando K, Kawarazaki H, Nagae A, Fujita M, Shimosawa T, Nagase M, Fujita T.
  • Journal Title: Hypertension 52 Pages: 287-94
  • Peer Reviewed
• [Journal Article] Paradoxical mineralocorticoid receptor activation and left ventricular diastolic dysfunction under high oxidative stress conditions. (2008)
  • Author(s): Wang H, Shimosawa T, Matsui H, Kaneko T, Ogura S, Uetake Y, Takenaka K, Yatomi Y, Fujita T.
  • Journal Title: J Hypertens 26 Pages: 1453-62
  • Peer Reviewed
• [Journal Article] Salt excess causes left ventricular diastolic dysfunction in rats with metabolic disorder. (2008)
  • Author(s): Matsui H, Ando K, Kawarazaki H, Nagae A, Fujita M, Shimosawa T Nagace M Fuiita T.
  • Journal Title: Hypertension 52 Pages: 287-94
  • Peer Reviewed
• [Journal Article] Paradoxical mineralocorticoid receptor activation and left ventricular diastolic dysfunction under high oxidative stress conditions. (2008)
  • Author(s): Wang. H, Shimosawa T, Matsui H, Kaneko T, Ogura S, Uetake Y, Takenaka K, Yatomi Y, Fuiita T.
  • Journal Title: Journal of Hypertension 26 Pages: 1453-62
  • Peer Reviewed
• [Presentation] Lox-1 aggravate vascular injury by western diet. (2010)
  • Author(s): Uetake Y, Shimosawa T, Mu S, Mori F, Fujita T.
  • Organizer: The 23^<RD> Scientific meeting of the International Society of Hypertension
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2010-09-29
• [Presentation] 肝臓とレニンアンジオテンシン系 メタボリックシンドロームにおける役割 (2010)
  • Author(s): 下澤達雄、上竹勇三郎、森典子、穆勝宇、神保りか、史安男、王紅、松井宏光、小倉彩世子、池田均、矢冨裕、藤田敏郎
  • Organizer: 第33回日本高血圧学会総会
  • Place of Presentation: 福岡
• [Presentation] LOX-1の過剰発現と食餌性の酸化ストレスの亢進が血管障害を惹起する (2010)
  • Author(s): 上竹勇三郎,下澤達雄,森典子,穆勝宇,史安男,藤田敏郎
  • Organizer: 第33回日本高血圧学会総会
  • Place of Presentation: 福岡
• [Presentation] Lox-1 aggravate vascular injury by western diet. (2010)
  • Author(s): Uetake Y, Shimosawa T, Mu S, Mori F, Fujita T.
  • Organizer: The 23^<RD> Scientific meeting of the International Society of Hypertension, Vancouver
  • Place of Presentation: Canada
• [Presentation] A role of the diet and LOX-1-induced oxidative stress in the onset of NASH. (2010)
  • Author(s): Uetake Y, Shimosawa T, Ikeda H, Yatomi Y, Fujita T.
  • Organizer: 14^<th> International Congress of Endocrinology(ICE2010)
  • Place of Presentation: Kyoto
• [Presentation] A role of the diet and LOX-1-induced oxidative stress in the onset of NASH. (2010)
  • Author(s): Uetake Y, Shimosawa T, Ikeda H, Yatomi Y, Fujita T.
  • Organizer: 14^<th> International Congress of Endocrinology (ICE2010)
  • Place of Presentation: Kyoto
• [Presentation] 心腎連関とRAAS (2009)
  • Author(s): 下澤達雄
  • Organizer: 第39回日本腎臓学会東部学術大会
  • Place of Presentation: 東京
• [Presentation] 食餌性の酸化ストレスが血圧の上昇およびLOX-1を介して血管障害を惹起する (2009)
  • Author(s): 上竹勇三郎,下澤達雄,松井宏光,森典子,小倉彩世子,王紅,穆勝宇,藤田敏郎
  • Organizer: 第32回日本高血圧学会総会
  • Place of Presentation: 大津
• [Presentation] 食餌性の酸化ストレスと血管障害に関する検討 (2009)
  • Author(s): 上竹勇三郎,下澤達雄,松井宏光,森典子,小倉彩世子,王紅,穆勝宇,藤田敏郎
  • Organizer: 第52回日本腎臓学会学術総会
  • Place of Presentation: 横浜
• [Presentation] 食餌性の酸化ストレスと血管障害に関する検討 (2008)
  • Author(s): 上竹勇三郎,下澤達雄,松井宏光,小倉彩世子,王紅,穆勝宇,藤田敏郎
  • Organizer: 第31回日本高血圧学会学術総会
  • Place of Presentation: 札幌
• [Presentation] LOX-1 aggravate vascular injury by western diet. (2008)
  • Author(s): Uetake Y, Shimosawa T, Matsui H, Mori F, Ogura S, Wang H, Mu S, Fujita T.
  • Organizer: 22^<nd> Scientific Meeting of International Society of Hypertension, Berlin
  • Place of Presentation: Germany
• [Presentation] 食餌性の酸化ストレスと血管障害に関する検討 (2008)
  • Author(s): 上竹勇三郎,下澤達雄,松井宏光,森典子,小倉彩世子,王紅,穆勝宇,藤田敏郎
  • Organizer: 第51回日本腎臓学会学術総会
  • Place of Presentation: 福岡
• [Presentation] A Role of the diet-induced oxidative stress in the onset of NASH. (2008)
  • Author(s): Uetake Y, Shimosawa T, Ikeda H, Yutaka Y, Fujita T.
  • Organizer: 43rd Annual Meeting of the European Association for the Study of the Liver (EASL)
  • Place of Presentation: Milan, Italy
• [Presentation] 食餌性の酸化ストレスと血管障害に関する検討. (2008)
  • Author(s): 上竹勇三郎,下澤達雄,松井宏光,小倉彩世子,王紅,穆勝宇,藤田敏郎
  • Organizer: 第31回日本高血圧学会学術総会
  • Place of Presentation: 札幌
• [Presentation] LOX-1 aggravates vascular injury by western diet. (2008)
  • Author(s): UetakeY, ShimosawaT, Matsui H, Mori F, Ogura S, Wang H, Mu S, Fujita T
  • Organizer: 22nd Scientific Meeting of International Society of Hypertension,
  • Place of Presentation: Berlin
• [Presentation] Role of the diet-induced oxidative stress in the onset of NASH. (2008)
  • Author(s): Uetake Y, Shimosawa T, Ikeda H. Yutaka Y. Fuiita T.
  • Organizer: 43rd Annual Meeting of the European Association for the Study of the Liver (EASL)
  • Place of Presentation: Milan
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