Impact of mitochondria reactive oxygen species in the pathogenesis of diabetic macro- and micro vascular complications.

• Project/Area Number: 18590995
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kumamoto University
• Principal Investigator: NISHIKAWA Takeshi Kumamoto University, Faculty of Medical and Phamaceutical sciences, Assistant Professor (70336212)
• Co-Investigator(Kenkyū-buntansha): NISHIDA Kenro Kumamoto University, Faculty of Medical and Phamaceutical sciences, Lecturer (50336244) ; MATSUMURA Takeshi Kumamoto University, University Hospital, Clinical Fellow (20398192) ; MOTOSHIMA Hiroyuki Kumamoto University, University Hospital, Clinical Fellow (40398201)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000); Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: Diabetes Mellitus / Diabetic complications / Mitochondria / Oxidative stress / MnSOD / PPARγ / MnSOD / PPARγアゴニスト

Research Abstract

We previously proposed that hyperglycemia-induced mitochondrial ROS overproduction is a key event in the development of diabetic complications. During 2006-2007, we have performed below project based on our hypothesis.
In this study, we established a novel transgenic mouse (eMnSOD-Tg), which specifically expressed MnSOD in endothelial cells, by employing a Tie2 promoter/enhancer, and investigated the impact of mitochondrial ROS production on diabetic retinopathy in vivo. Using immunohistochemistry, overexpression of MnSOD in endothelial cells was confirmed in eMnSOD-Tg mice. By introduction of diabetes by streptozotocin, levels of urinary 8-hydroxydeoxyguanosine, a marker of mitochondrial oxidative stress, and expression of VEGF mRNA and protein and fibronectin mRNA in retinas were increased in wild-type littermates. However, these observations were ameliorated in eMnSOD-Tg mice, although control and eMnSOD-Tg mice showed a comparable level of hyperglycemia. In the present study, we newly developed a line of transgenic mice, which specifically express MnSOD in endothelium. In addition, overexpression of mitochondrial-specific SOD in endothelium could prevent diabetic retinopathy in vivo.

Research Products

• [Journal Article] Endothelial MnSOD overexpression prevents retinal VEGF expression in diabetic mice (2008)
  • Author(s): Goto H, et. al.
  • Journal Title: Biochem Biophys Res Commun 366 Pages: 814-820
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Oxidized low density lipoprotein activates peroxisome proliferator-activated receptor-α(PPARα)and PPARγ through MAPK-dependent COX-2 expression in macrophages (2008)
  • Author(s): Taketa K, et. al.
  • Journal Title: J Biol Chem 283 Pages: 9852-9862
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Endothelial MnSOD overexpression prevents retinal VEGF expression in diabetic mice (2008)
  • Author(s): Goto, H., Nishikawa, T.*, Sonoda, K., Kondo, T., Kukidome, D., Fujisawa, K., Yamashiro, T., Motoshima, H., Matsumura, T., Tsuruzoe, K., Araki, E.
  • Journal Title: Biochem Biophys Res Commun 366 Pages: 814-820
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Oxidized low density lipoprotein activates peroxisome proliferator-activated receptor-a(PPARa) and PPARy through MAPK-dependent COX-2 expression in macrophages. (2008)
  • Author(s): Taketa, K., Matsumura, T., Yano, M., Ishii, N., Senokuchi, T., Motoshima, H., Murata, Y., Kim-Mitsuyama, S., Kawada, T., Itabe, H., Takeya, M., Nishikawa, T., Tsuruzoe, K., Araki, E.
  • Journal Title: J Biol Chem 283 Pages: 9852-9862
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] (2008)
  • Author(s): Goto H
  • Journal Title: Biochem Biophys Res Commun 366 Pages: 814-820
  • Peer Reviewed
• [Journal Article] Impact of mitochondrial ROS production in the pathogenesis of diabetic mellitus and its complications (2007)
  • Author(s): Nishikawa T, et. al.
  • Journal Title: Antioxid Redox Signal 9 Pages: 343-353
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Troglitazone inhibits oxidized low-density lipoprotein-induced macrophage proliferation:impact of the suppression of nuclear translocation of ERK1/2 (2007)
  • Author(s): Yano M, et. al.
  • Journal Title: Atherosclerosis 191 Pages: 22-32
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Statins activate peroxisome proliferator-activated receptorgamma through extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2 expression in macrophages (2007)
  • Author(s): Yano M, et. al.
  • Journal Title: Circ Res 100 Pages: 1442-1451
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Impact of mitochondrial ROS production on diabetic vascular complications (2007)
  • Author(s): Nishikawa T, et. al.
  • Journal Title: Diabetes Res Clin Prat 77S
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Impact of mitochondrial ROS production in the pathogenesis of insulin resistance (2007)
  • Author(s): Nishikawa T, et. al.
  • Journal Title: Diabetes Res Clin Prat 77S
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Impact of mitochondrial ROS production in the pathogenesis of diabetic mellitus and its complications.(* corresponding author) (2007)
  • Author(s): Nishikawa, T.*, Araki, E.
  • Journal Title: Antioxid Redox Signal 9 Pages: 343-353
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Impact of mitochondrial ROS production on diabetic vascular complications.(* corresponding author) (2007)
  • Author(s): Nishikawa, T.*, Kukidome, D., Sonoda, K., Fujisawa, K., Matsuhisa, T., Motoshima, H., Matsumura, T., Araki, E.
  • Journal Title: Diabetes Res Clin Prat 77S
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Impact of mitochondrial ROS production in the pathogenesis of insulin resistance.(* corresponding author) (2007)
  • Author(s): Nishikawa, T.*, Kukidome, D., Sonoda, K., Fujisawa, K., Matsuhisa, T., Motoshima, H., Matsumura, T., Araki, E.
  • Journal Title: Diabetes Res Clin Pract77S
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Troglitazone inhibits oxidized low-density lipoprotein-induced macrophage proliferation : impact of the suppression of nuclear translocation of ERK1/2 (2007)
  • Author(s): Yano, M., Matsumura, T., Senokuchi, T., Ishii, N., Motoshima, H., Taguchi, T., Matsuo, T., Sonoda, K., Kukidome, D., Sakai, M., Kawada, T., Nishikawa, N., Araki, E.
  • Journal Title: Atherosclerosis 191 Pages: 22-32
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Statins activate peroxisome proliferator-activated receptor gamma through extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2 expression in macrophages. (2007)
  • Author(s): Yano, M., Matsumura, T., Senokuchi, T., Ishii, N., Murata, Y., Taketa, K., Motoshima, H., Taguchi, T., Sonoda, K., Kukidome, D., Takuwa, Y., Kawada, T., Brownlee, M., Nishikawa, T., Araki, E.
  • Journal Title: Circ Res 100 Pages: 1442-1451
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Impact of mitochondrial ROS production in the pathogenesis of diabetic mellitus and its complications. (2007)
  • Author(s): Nishikawa T
  • Journal Title: Antioxid Redox Signal 9 Pages: 343-353
  • Peer Reviewed
• [Journal Article] (2007)
  • Author(s): Nishikawa T
  • Journal Title: Diabetes Res Clin Prat 77S
• [Journal Article] Impact of mitochondrial ROS production in the pathogenesis of insulin resistance. (2007)
  • Author(s): Nishikawa T
  • Journal Title: Diabetes Res Clin Prat 77S
• [Journal Article] Troglitazone inhibits oxidized low-density lipoprotein-induced macrophage proliferation: impact of the suppression of nuclear translocation of ERK 1/2. (2007)
  • Author(s): Yano M
  • Journal Title: Atherosclerosis 191 Pages: 22-32
  • Peer Reviewed
• [Journal Article] Statins activate peroxisome proliferator-activated receptor gamma through extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2 expression in macrophages. (2007)
  • Author(s): Yano M
  • Journal Title: Circ Res 100 Pages: 1442-1451
  • Peer Reviewed
• [Journal Article] Troglitazone Inhibits Oxidized Low-Density Lipoprotein-Induced Macrophage Proliferation : Impact of the Suppression of Nuclear Translocation of ERK 1/2 (2007)
  • Author(s): Yano M, Nishikawa T et al.
  • Journal Title: Atherosclerosis 191 Pages: 22-32
• [Journal Article] Impact of mitochondrial ROS production in the pathogenesis of diabetic mellitus and its complications. (2007)
  • Author(s): Nishikawa T, Araki E
  • Journal Title: Antioxid.Redox Signal 9 Pages: 343-353
• [Journal Article] Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production possibly through induction of MnSOD and promotion of mitochondrial biogenesis in HUVECs. (2006)
  • Author(s): Kukidome D, Nishikawa T et al.
  • Journal Title: Diabetes 55 Pages: 120-127
• [Journal Article] Impact of mitochondrial reactive oxygen species (ROS) and apoptosis signal-regulating kinase 1 (ASK1) on insulin signaling. (2006)
  • Author(s): Imoto K, Kukidome D, Nishikawa T et al.
  • Journal Title: Diabetes 55 Pages: 1197-1204
• [Journal Article] 糖尿病合併症の分子生物学-ミトコンドリア由来活性酸素の意義- (2006)
  • Author(s): 西川武志
  • Journal Title: 日本体質医学会誌 68 Pages: 119-123
• [Journal Article] 糖尿病合併症におけるミトコンドリア由来活性酸素の意義 (2006)
  • Author(s): 西川武志
  • Journal Title: 糖尿病合併症学会誌 20 Pages: 140-144
• [Presentation] 糖尿病合併症発症機構解明への取り組み-ミトコンドリア由来活性酸素の役割 (2008)
  • Author(s): 西川 武志
  • Organizer: 第53回日本臨床検査医学会中国・四国支部総会
  • Place of Presentation: 岡山
  • Year and Date: 2008-02-09
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Pathogenic role of mitochondrial ROS in diabetes and its complications (2007)
  • Author(s): Nishikawa T
  • Organizer: The 14th Japan-Korea Symposium on Diabetes Mellitus
  • Place of Presentation: Kyoto
  • Year and Date: 2007-10-05
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 体質医学からみた血管病代謝内分泌(基礎)の立場から-血管病発症におけるミトコンドリア由来活性酸素の役割 (2007)
  • Author(s): 西川 武志
  • Organizer: 第57回日本体質学会総会
  • Place of Presentation: 大分
  • Year and Date: 2007-09-29
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Pathogenic role of mitochondrial ROS in diabetes and its complications (2007)
  • Author(s): Nishikawa, T.
  • Organizer: The 14th Japan-Korea Symposium on Diabetes Mellitus
  • Place of Presentation: Kyoto, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] 体質医学からみた血管病 代謝内分泌(基礎)の立場から-血管病発症におけるミトコンドリア由来活性酸素の役割 (2007)
  • Author(s): 西川 武志
  • Organizer: 第57回日本体質学会総会
  • Place of Presentation: 大分
• [Presentation] Pathogenic role of mitochondrial ROS in diabetes and its complications (2007)
  • Author(s): Nishikawa T
  • Organizer: 14th Japan-Korea Symposium on Diabetes Mellitus
  • Place of Presentation: Kyoto
• [Presentation] 田原坂スタディにおける介入指導効果の持続性の検討 (2007)
  • Author(s): 西川 武志
  • Organizer: 第45回日本糖尿病学会九州地方会
  • Place of Presentation: 宮崎
• [Presentation] 合併症のメカニズム (2006)
  • Author(s): 西川 武志
  • Organizer: 第44回日本糖尿病学会九州地方会
  • Place of Presentation: 熊本
  • Year and Date: 2006-10-13
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 酸化ストレスと糖尿病合併症 (2006)
  • Author(s): 西川 武志
  • Organizer: 第41回糖尿病学の進歩
  • Place of Presentation: 札幌
  • Year and Date: 2006-09-29
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Impact of mitochondrial ROS production in the pathogenesis of diabetic vascular complications (2006)
  • Author(s): Nishikawa T
  • Organizer: Severance Hospital Diabetes Center 10th Anniversary International Symposium on Diabetes Mellitus
  • Place of Presentation: Seoul
  • Year and Date: 2006-05-18
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Impact of mitochondrial ROS production in the pathogenesis of diabetic vascular complications. (2006)
  • Author(s): Nishikawa, T.
  • Organizer: Severance Hospital Diabetes Center 10th Anniversary International Symposium on Diabetes Mellitus
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2006-05-18
  • Description: 「研究成果報告書概要(欧文)」より