AGE/RAGE in metabolic and vascular inflammation

• Project/Area Number: 26461371
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Hyogo Medical University
• Principal Investigator: Koyama Hidenori 兵庫医科大学, 医学部, 教授 (80301852)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 糖尿病 / 動脈硬化 / 炎症 / RAGE / 血管炎症 / RAGE shedding / TNF-α / 小胞体ストレス

Outline of Final Research Achievements

Pathophysiological regulation and underlying mechanisms of RAGE shedding are scarcely understood. We showed here that in endothelial-specific human RAGE transgenic mice, human sRAGE level was markedly increased following TNFα. In RAGE overexpressed human endothelial cells, TNFα markedly induced RAGE shedding, which was dependent on ADAM10. TNFα transiently induced ATF4, while knockdown of ATF4 abrogated RAGE shedding. Pro-and activated forms of ADAM10 were also decreased by ATF4 knockdown, whereas inhibition of other ER components was without an effect. Notably, though the ER stressors induced marked and sustained expression of ATF4 and XBP-1, they did not induce RAGE shedding. ATF4 inhibition did not affect TNFα-stimulated MMP9 expression, which was completely dependent on JNK activation, while inhibition of JNK was partially effective to suppress RAGE shedding. Collectively, TNFα induce RAGE shedding in ATF4 dependent manner.

Research Products

• [Journal Article] Serum Macro TSH level is associated with sleep quality in patients with cardiovascular risks: HSCAA Study. (2017)
  • Author(s): Kadoya M Koyama S, Morimoto A, Miyoshi A, Kakutani M, Hamamoto K, Kurajoh M, Shoji T, Moriwaki Y, Koshiba M, Yamamoto T, Inaba M, Namba M, Koyama H
  • Journal Title: Scientifi Report Volume: 7 Issue: 1 Pages: 44387-44387
  • DOI: 10.1038/srep44387
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Extension of recovery time from fatigue by repeated rest with short-term sleep during continuous fatigue load: Development of chronic fatigue model. (2016)
  • Author(s): Kanzaki, A., Okauchi, T., Hu, D., Shingaki, T., Katayama, Y., Koyama, H., Watanabe, Y., and Cui Y.L.
  • Journal Title: J Neurosci Res Volume: 94 Issue: 5 Pages: 424-429
  • DOI: 10.1002/jnr.23718
  • Peer Reviewed / Open Access
• [Journal Article] Associations of sleep quality and awake physical activity with fluctuations in nocturnal blood pressure in patients with cardiovascular risk factors. (2016)
  • Author(s): Kadoya M, Koyama H, Kurajoh M, Naka M, Miyoshi A, Kanzaki A, Kakutani-Hatayama M, Shoji T, Moriwaki Y, Yamamoto T, Inaba M, Namba M
  • Journal Title: PLoS ONE Volume: 11(5) Issue: 5 Pages: e0155116-e0155116
  • DOI: 10.1371/journal.pone.0155116
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Plasma leptin concentration is associated with fatigue severity in patients with cardiovascular risk factors - HSCAA study. (2016)
  • Author(s): Kurajoh M, Kadoya M, Morimoto A, Naka M, Miyoshi A, Kanzaki A, Kakutani-Hatayama M, Hamamoto K, Shoji T, Moriwaki Y, Yamamoto T, Inaba M, Namba M, Koyama H
  • Journal Title: Psychoneuroendocrinology Volume: 74 Pages: 7-12
  • DOI: 10.1016/j.psyneuen.2016.08.016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Association of Erythropoietin Resistance with Fatigue in Hemodialysis Patients: A Cross-Sectional Study. (2016)
  • Author(s): Yamasaki A1, Yoda K, Koyama H, Yamada S, Tsujimoto Y, Okuno S, Okada S, Inaba M
  • Journal Title: Nephron Volume: 134(2) Pages: 95-102
  • Peer Reviewed
• [Journal Article] Oncostatin M promotes osteoblastic differentiation of human vascular smooth muscle cells through JAK3-STAT3 pathway (2015)
  • Author(s): Kakutani Y, Shioi A, Shoji T, Okazaki H, Koyama H, Emoto M, Inaba M
  • Journal Title: J Cell Biochem Volume: 印刷中 Issue: 7 Pages: 1325-1333
  • DOI: 10.1002/jcb.25088
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Plasma leptin level is associated with cardiac autonomic dysfunction in patients with type 2 diabetes: HSCAA study (2015)
  • Author(s): Kurajoh M, Koyama H, Kadoya M, Naka M, Miyoshi A, Kanzaki A, Kakutani-Hatayama M, Okazaki H, Shoji T, Moriwaki Y, Yamamoto T, Emoto M, Inaba M, Namba M
  • Journal Title: Cardiovascular Diabetology Volume: 14 Issue: 1 Pages: 117-117
  • DOI: 10.1186/s12933-015-0280-6
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Anaplastic Thyroid Carcinoma Accompanied by Uncontrollable Eosinophilia (2015)
  • Author(s): Shiraishi J, Koyama H, Seki M, Hatayama M, Naka M, Kurajoh M, Okazaki H, Shoji T, Moriwaki Y, Yamamoto T, Tsuchida Y, Tsukamoto Y, Hirota S, Onoda N, Namba M.
  • Journal Title: Internal Medicine Volume: 54 Issue: 6 Pages: 611-616
  • DOI: 10.2169/internalmedicine.54.3446
  • NAID: 130004903072
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Partial HPRT Deficiency with a Novel Mutation of the <i>HPRT</i> Gene in Combination with Four Previously Reported Variants Associated with Hyperuricemia (2015)
  • Author(s): Kurajoh M, Koyama H, Hatayama M, Okazaki H, Shoji T, Moriwaki Y, Yamamoto T, Nakayama T, Namba M
  • Journal Title: Internal Medicine Volume: 54 Issue: 12 Pages: 1523-1526
  • DOI: 10.2169/internalmedicine.54.3290
  • NAID: 130005075957
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Sleep, cardiac autonomic function, and carotid atherosclerosis in patients with cardiovascular risks: HSCAA Study (2015)
  • Author(s): Kadoya M, Koyama H, Kurajoh M, Kanzaki A, Hatayama M, Okazaki H, Shoji T, Moriwaki Y, Yamamoto T, Emoto M, Inaba M, Namba M
  • Journal Title: Atherosclerosis Volume: 238 Issue: 2 Pages: 409-414
  • DOI: 10.1016/j.atherosclerosis.2014.12.032
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of nutritional supplementation on fatigue, and autonomic and immune dysfunction in patients with end-stage renal disease: a randomized, double-blind, placebo-controlled, multicenter trial (2015)
  • Author(s): F ukuda S, Koyama H, Kondo K, Fujii H, Hirayama Y, Tabata T, Okamura M, Yamakawa T, Okada S, Hirata S, Kiyama H, Kajimoto O, Watanabe Y, Inaba M, Nishizawa Y
  • Journal Title: PLoS ONE Volume: 10 Issue: 3 Pages: e0119578-e0119578
  • DOI: 10.1371/journal.pone.0119578
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of effects of pioglitazone and glimepiride on plasma soluble RAGE and RAGE expression in peripheral mononuclear cells in type 2 diabetes: Randomized controlled trial (PioRAGE) (2014)
  • Author(s): Koyama H, Tanaka S, Monden M, Shoji T, Morioka T, Fukumoto S, Mori K, Emoto M, Shoji T, Fukui M, Fujii H, Nishizawa Y, Inaba M
  • Journal Title: Atherosclerosis Volume: 234 Issue: 2 Pages: 329-334
  • DOI: 10.1016/j.atherosclerosis.2014.03.025
  • Peer Reviewed
• [Journal Article] Plasma Brain-Derived Neurotrophic Factor and Reverse Dipping Pattern of Nocturnal Blood Pressure in Patients with Cardiovascular Risk Factors (2014)
  • Author(s): Kadoya M, Koyama H, Kanzaki A, Kurajoh M, Hatayama M, Shiraishi M, Okazaki H, Shoji T, Moriwaki Y, Yamamoto T, Inaba M, Namba M
  • Journal Title: PLoS One Volume: 9 Issue: 8 Pages: e105977-e105977
  • DOI: 10.1371/journal.pone.0105977
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 終末糖化産物受容体(RAGE)は飽和脂肪酸による血管内皮細胞のアポトーシス誘導を増強する (2016)
  • Author(s): 庄司拓仁、児山幸恵、三好晶雄、角谷 学、森脇優司、山本靖彦、小山英則
  • Organizer: 第48回日本動脈硬化学会
  • Place of Presentation: 京王プラザホテル（東京都・新宿区)
  • Year and Date: 2016-07-15
• [Presentation] 血管内皮の炎症と可溶性RAGE産生機序の検討 (2016)
  • Author(s): 三好晶雄、庄司拓仁、児山幸恵、笹川真砂世、角谷 学、森脇優司、山本靖彦、稲葉雅章、小山英則
  • Organizer: 第48回日本動脈硬化学会
  • Place of Presentation: 京王プラザホテル（東京都・新宿区)
  • Year and Date: 2016-07-14
• [Presentation] 血管内皮の炎症と可溶性RAGE産生機序の検討 (2016)
  • Author(s): 三好晶雄、庄司拓仁、児山幸恵、笹川（門田）真砂世、角谷学、森脇優司、山本靖彦、稲葉雅章、小山英則
  • Organizer: 日本動脈硬化学会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2016-07-14
• [Presentation] マクロTSHは血糖変動と関連し2型糖尿病で上昇する―HSCAA研究― (2016)
  • Author(s): 角谷学，小山英則，森本晶子，中真理子，三好晶雄，角谷美樹，濱本佳恵，藏城雅文，庄司拓仁，小柴賢洋，森脇優司，難波光義
  • Organizer: 第59回日本糖尿病学会
  • Place of Presentation: 国立京都国際会館(京都府・京都市)
  • Year and Date: 2016-05-21
• [Presentation] 血漿Brain-derived growth factor濃度は慢性腎臓病の発症を予測する：HSCAA study (2016)
  • Author(s): 藏城雅文、小山英則、中真理子、角谷 学、森本晶子、三好晶雄、角谷美樹、濱本佳恵、庄司拓仁、森脇優司、山本徹也、難波光義
  • Organizer: 第89回日本内分泌学会
  • Place of Presentation: 国立京都国際会館(京都府・京都市)
  • Year and Date: 2016-04-23
• [Presentation] ヒトにおけるマクロTSHと睡眠障害に関する検討 (2016)
  • Author(s): 角谷 学、小山英則、森本晶子、中真理子、三好晶雄、角谷美樹、濱本佳恵、藏城雅文、庄司拓仁、小柴賢洋、森脇優司、難波光義
  • Organizer: 第89回日本内分泌学会
  • Place of Presentation: 国立京都国際会館(京都府・京都市)
  • Year and Date: 2016-04-23
• [Presentation] Parathyroid hyperplasia induced by uniparental disomy in a MEN1 patient with a frame-shift mutation (2016)
  • Author(s): Koyama H, Miyoshi A, Yoshikawa Y, Hashimoto-Tamaoki T, Enomoto Y, Miyoshi Y, Kadoya M, Kurajoh M, Shoji T, Moriwaki Y, Yamamoto T, Namba M
  • Organizer: The 13th Internationa Congress of Human Genetics
  • Place of Presentation: 国立京都国際会館(京都府・京都市)
  • Year and Date: 2016-04-06
  • Int'l Joint Research
• [Presentation] Inflammation and shedding of receptor for AGE (RAGE): roles of ER stress. (2014)
  • Author(s): Koyama H, Monden M, Shoji T, Yamamoto Y, Yamamoto H, Inaba M, Namba M
  • Organizer: 9th Metabolc syndrome, Type 2 Diaetes and Atherosclerosis Congress
  • Place of Presentation: kyoto, Japan
  • Year and Date: 2014-09-12 – 2014-09-14
• [Presentation] lasma brain-derived neurotrophic factor, cardiac autonomic function and nocturnal changes in blood pressure: implications in nocturnal hypertension in diabetes. (2014)
  • Author(s): Kadoya M, Koyama H, Kurajoh M, Hatayama M, Okazaki H, Shoji T, Moriwaki Y, Yamamoto T, Namba M
  • Organizer: 9th Metabolc syndrome, Type 2 Diaetes and Atherosclerosis Congress
  • Place of Presentation: kyoto, Japan
  • Year and Date: 2014-09-12 – 2014-09-14
• [Presentation] 2型糖尿病患者のBrain-Derived Neurotrophic Factor 及び自律神経機能と夜間血圧変動の関連 (2014)
  • Author(s): 角谷 学、小山英則、蔵城雅文、白石 順、岡崎博一、神埼暁慶、畑山美樹、角田千尋、庄司拓仁、森脇優司、山本徹也、難波光義
  • Organizer: 第57回日本糖尿病学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-24
• [Presentation] 糖尿病患者でのレプチンと自律神経機能との関連 (2014)
  • Author(s): 蔵城雅文、小山英則、角谷 学、白石 順、岡崎博一、神埼暁慶、畑山美樹、角田千尋、庄司拓仁、森脇優司、山本徹也、難波光義
  • Organizer: 第57回日本糖尿病学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-23
• [Presentation] 2型糖尿病患者における呼吸商の検討：心血管疾患既往および頸動脈硬化との関連 (2014)
  • Author(s): 庄司拓仁、小山英則、畑山美樹、神埼暁慶、白石 順、角谷 学、角田千尋、岡崎博一、蔵城雅文、山本徹也、森脇優司、難波光義
  • Organizer: 第57回日本糖尿病学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-23
• [Presentation] Brain-Derived Neurotrophic Factor とriser型夜間高血圧との関連 (2014)
  • Author(s): 角谷 学、小山英則、神埼暁慶、蔵城雅文、畑山美樹、白石 順、角田千尋、岡崎博一、庄司拓仁、森脇優司、山本徹也、難波光義
  • Organizer: 第87回日本内分泌学会
  • Place of Presentation: 福岡
  • Year and Date: 2014-04-25
• [Book] 治療薬 UP-TO-DATE 2017 (2017)
  • Author(s): 美内雅之、小山英則、難波光義
  • Publisher: メディカルレビュー社
• [Book] 新時代の臨床糖尿病学(下)－よりよい血糖管理をめざして－ (2016)
  • Author(s): 小山英則
  • Publisher: 日本臨床社
• [Book] もう困らない 病棟での血糖コントロール (2016)
  • Author(s): 松尾俊宏、勝野朋幸、小山英則
  • Publisher: じほう
• [Book] 糖尿病性腎症の治療のポイント (2016)
  • Author(s): 角谷美樹、小山英則
  • Publisher: 医薬ジャーナル社