The role of Keap1-Nrf2 system in obesity-induced pancreatic beta-cell dysfunctions

• Project/Area Number: 24790306
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: URUNO Akira 東北大学, 医学(系)研究科(研究院), 講師 (90396474)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 膵β細胞 / 糖尿病 / 酸化ストレス / Keap1-Nrf2システム / Nrf2

Research Abstract

The Keap1-Nrf2 system contributes to protect against environmental stress including oxidative stress. Diabetes mellitus is a metabolic disorder with severe complications, and the protection from pancreatic beta-cell dysfunction is important for the suppression of onset and progression of diabetes mellitus. Activation Keap1-Nrf2 system strongly suppressed pancreatic beta-cell dysfunction in obesity-induced diabetic model mice. Nrf2 activation induced antioxidant genes in isolated islets from obesity-induced diabetic model mice. These results indicate that the Keap1-Nrf2 system probably is a target for the protection of pancreatic beta-cells against obesity-induced dysfunctions.

Research Products

• [Journal Article] Angiotensin II receptor blockers differentially affect CYP11B2 expression in human adrenal H295R cells. (2014)
  • Author(s): Matsuda K, Uruno A, Kogure N, Sugawara K, Shimada H, Nezu M, Saito-Ito T, Iki Y, Kudo M, Shimizu K, Sato I, Yoshikawa T, Satoh F, Ito R, Yokoyama A, Rainey WE, Saito-Hakoda A, Ito S, Sugawara A.
  • Journal Title: Mol Cell Endocrinol. Volume: 383(1-2) Issue: 1-2 Pages: 60-68
  • DOI: 10.1016/j.mce.2013.12.004
  • Peer Reviewed
• [Journal Article] Nrf2 protects pancreatic β-cells from oxidative and nitrosative stress in diabetic model mice (2014)
  • Author(s): Yagishita Y, Fukutomi T, Sugawara A, Kawamura H, Takahashi T, Pi J, Uruno A, and Yamamoto M.
  • Journal Title: Diabetes Volume: 63 Issue: 2 Pages: 605-618
  • DOI: 10.2337/db13-0909
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] ARB affects nicotine-induced gene expression profile in human coronary artery endothelial cells. (2014)
  • Author(s): Kudo M, Matsuda K, Sugawara K, Iki Y, Kogure N, Saito-Ito T, Shimizu K, Sato I, Yoshikawa T, Uruno A, Yokoyama A, Saito-Hakoda A, Ito S, Sugawara A.
  • Journal Title: World Journal of Hypertension. Volume: 4(1) Issue: 1 Pages: 7-14
  • DOI: 10.5494/wjh.v4.i1.7
  • Peer Reviewed
• [Journal Article] The Keap1-Nrf2 system prevents onset of diabetes mellitus (2013)
  • Author(s): Uruno A, Furusawa Y, Yagishita Y, Fukutomi T, Muramatsu H, Negishi T, Sugawara A, Kensler TW, Yamamoto M
  • Journal Title: Mol Cell Biol Volume: 33 Issue: 15 Pages: 2996-3010
  • DOI: 10.1128/mcb.00225-13
  • Peer Reviewed
• [Journal Article] Keap1-Nrf2システムによる惇8細胞保護作用 (2013)
  • Author(s): 5. 宇留野晃
  • Journal Title: 日本応用酵素協会誌 Volume: 48 Pages: 68-69
  • URL: http://www.mt-pharma.co.jp/jfae/
• [Journal Article] 糖尿病発症における酸化ストレスの役割 (2012)
  • Author(s): 6. 宇留野晃
  • Journal Title: 日本応用酵素協会誌 Volume: 47 Pages: 72-72
  • URL: http://www.mt-pharma.co.jp/jfae/
• [Journal Article] Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma (2012)
  • Author(s): Inoue D, Suzuki T, Mitsuishi Y, Miki Y, Suzuki S, Sugawara S, Watanabe M, Sakurada A, Endo C, Uruno A, Sasano H, Nakagawa T, Satoh K, Tanaka N, Kubo H, Motohashi H, Yamamoto M
  • Journal Title: Cancer Sci Volume: 103 Issue: 4 Pages: 760-766
  • DOI: 10.1111/j.1349-7006.2012.02216.x
  • Peer Reviewed
• [Journal Article] Effects of PPARγ agonists against vascular and renal dysfunction (2012)
  • Author(s): Sugawara A, Uruno A, Matsuda K, Saito-Ito T, Funato T, Saito-Hakoda A, Kudo M, Ito S.
  • Journal Title: Curr Mol Pharmacol Volume: 5 Issue: 2 Pages: 248-254
  • DOI: 10.2174/1874467211205020248
  • Peer Reviewed
• [Presentation] Nrf2 protects pancreaticβ- cells from oxidative and nitrosative stress in diabetic model mice (2014)
  • Author(s): Yagishita Y, Fukutomi T, Sugawara A, Pi J, Uruno A, Yamamoto M
  • Organizer: The Environmental Response IV (Oral presentation of selected poster session)
  • Place of Presentation: sendai
  • Year and Date: 2014-03-01
• [Presentation] The Keap1-Nrf2 system prevents onset of diabetes mellitus (2014)
  • Author(s): Uruno A, Furusawa Y, Yagishita Y, Fukutomi T, Muramatsu H, Negishi T, Sugawara A, Kensler T. W., Yamamoto M
  • Organizer: The Environmental Response IV
  • Place of Presentation: sendai
  • Year and Date: 2014-02-28
• [Presentation] The Keap1-Nrf2 system prevents onset of diabetes mellitus. (2014)
  • Author(s): Uruno A, Furusawa Y, Yagishita Y, Fukutomi T, Muramatsu H, Negishi T, Sugawara A, Kensler TW, Yamamoto M.
  • Organizer: The Environmental Response IV
  • Place of Presentation: Sendai
• [Presentation] Nrf2 protects pancreatic β-cells from oxidative and nitrosative stress in diabetic model mice. (2014)
  • Author(s): Yagishita Y, Fukutomi T, Sugawara A, Pi J, Uruno A, Yamamoto M.
  • Organizer: The Environmental Response IV
  • Place of Presentation: Sendai
• [Presentation] Keap1-Nrf2システムによる惇8細胞保護作用 (2013)
  • Author(s): 3. 柳下陽子、宇留野晃、福富俊明、菅原明、川村仁、高橋哲、山本雅之
  • Organizer: 日本生化学会東北支部第79回例
  • Place of Presentation: 仙台
  • Year and Date: 2013-05-11
• [Presentation] 種々のレチノイドX受容体(RXR)アゴニストは、AtT20細胞の増殖・アポトーシス・POMC発現・ACTH分泌に異なる影響を及ぼす (2013)
  • Author(s): 4. 箱田明子、宇留野晃、清水恭子、伊藤貴子、萱岐裕子、吉川雄朗、松田謙、工藤正孝、影近弘之、岩崎泰正、伊藤貞嘉、菅原明
  • Organizer: 第86回日本内分泌学会学術総会
  • Place of Presentation: 仙台
  • Year and Date: 2013-04-27
• [Presentation] ニコチンのヒト冠動脈血管内皮細胞の遺伝子発現に及ぼす影響ならびにそれに対するARBの効果 (2013)
  • Author(s): 5. 萱岐裕子、工藤正孝、伊藤貴子、菅原香織、松田謙、小暮直敬、皆川敬治、勝木将人、佐藤郁子、宇留野晃、清水恭子、吉川雄朗、箱田明子、伊藤貞嘉、菅原明
  • Organizer: 第86回日本内分泌学会学術総会
  • Place of Presentation: 仙台
  • Year and Date: 2013-04-26
• [Presentation] 高血糖刺激はヒト副腎H295R細胞における118-水酸化酵素遺伝子(CYP11B1)発現を誘導する (2013)
  • Author(s): 6.菅原香織、伊藤貴子、小暮直敬、皆川敬治、萱岐裕子、勝木将人、宇留野晃、佐藤郁子、田中智博、太田期、木谷優介、塚田晃也、大熊崇生、角田亮、清水恭子、工藤正孝、松田謙、箱田明子、伊藤貞嘉、菅原明
  • Organizer: 第86回日本内分泌学会学術総会
  • Place of Presentation: 仙台
  • Year and Date: 2013-04-25
• [Presentation] 高血糖刺激は副腎アルドステロン合成酵素の発現をT型Caチャネルの発現増加を介して誘導す (2013)
  • Author(s): 7. 小暮直敬、伊藤貴子、菅原香織、松田謙、萱岐裕子、佐藤郁子、皆川敬治、勝木将人、清水恭子、吉川雄朗、工藤正孝、宇留野晃、箱田明子、伊藤貞嘉、菅原明
  • Organizer: 第86回日本内分泌学会学術総会
  • Place of Presentation: 仙台
  • Year and Date: 2013-04-25
• [Presentation] Keap1-Nrf2システムによる膵β細胞保護作用 (2013)
  • Author(s): 柳下陽子、宇留野晃、福富俊明、菅原明、川村仁、高橋哲、山本雅之
  • Organizer: 第77回日本生化学会東北支部会
  • Place of Presentation: 仙台
• [Presentation] Retinoid X receptor agonists differentially affect proliferation, apoptosis, and ACTH secretion/POMC gene expression in AtT20 corticotroph cells (2012)
  • Author(s): Saito-Hakoda A, Uruno A, Shimizu K, Kudo M, Saito-Ito T, Yoshikawa T, Matsuda K, Fujiwara I, Kagechika H, Iwasaki Y, Ito S, Sugawara A
  • Organizer: The Endocrine Society 94th Annual Meeting
  • Place of Presentation: Houston, USA
  • Year and Date: 2012-06-23
• [Presentation] Telmisartan stimulates aldosterone synthase gene (CYP11B2) expression via the CaMK - mediated induction of NURR1 (2012)
  • Author(s): Matsuda K, Uruno A, Saito-Ito T, Shimizu K, Kudo M, Satoh F, Yoshikawa T, Saito-Hakoda A, Ito S, Sugawara A
  • Organizer: The Endocrine Society 94th Annual Meeting
  • Place of Presentation: Houston, USA
  • Year and Date: 2012-06-23
• [Presentation] High glucose stimulates aldosterone synthase gene (CYP11B2) expression in human adrenal H295R cells (2012)
  • Author(s): Saito, Ito T, Matsuda K, Uruno A, Shimizu K, Nakamura M, Takahashi R, Yoshikawa T, Kudo M, Saito, Hakoda A, Ito S, Sugawara
  • Organizer: The Endocrine Society 94th Annual Meeting
  • Place of Presentation: Houston, USA
  • Year and Date: 2012-06-23
• [Presentation] レチノイン酸受容体(RAR)αはNeuroD1・Tpitを介してPOMC遺伝子発現を充進する (2012)
  • Author(s): 11. 宇留野晃、箱田明子、松田謙、清水恭子、伊藤貴子、工藤正孝、岩崎泰正、伊藤貞嘉、菅原明
  • Organizer: 第85回日本内分泌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-04-21
• [Presentation] 全トランスレチノイン酸(ATRA)と合成レチノイドAm80は、血球・血管内皮間接着ならびに血球表面CD38発現に異なる影響を及ぼす (2012)
  • Author(s): 12. 宇留野晃、松田謙、吉川雄朗、箱田明子、伊藤貞嘉、岡本宏、菅原明
  • Organizer: 第85回日本内分泌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-04-21
• [Presentation] 各アンジオテンシンII受容体桔抗薬(ARB)はアルドステロン合成酵素(CYP11B2)発現に異なる影響を及ぼす(第三報) (2012)
  • Author(s): 13. 松田謙、宇留野晃、伊藤貴子、清水恭子、吉川雄朗、箱田明子、工藤正孝、佐藤文俊、伊藤貞嘉、菅原明
  • Organizer: 第85回日本内分泌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-04-21
• [Presentation] GLP-1受容体アゴニストの冠動脈血管内皮細胞の遺伝子発現に及ぼす影響の検討 (2012)
  • Author(s): 14. 工藤正孝、松田謙、箱田明子、伊藤貴子、清水恭子、佐藤文俊、宇留野晃、伊藤貞嘉、菅原明
  • Organizer: 第85回日本内分泌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-04-20
• [Presentation] アルドステロン合成酵素および118-水酸化酵素転写解析系として使用可能な新規安定株の作製 (2012)
  • Author(s): 15. 松田謙、宇留野晃、伊藤貴子、清水恭子、工藤正孝、箱田明子、吉川雄朗、佐藤文俊、伊藤貞嘉、菅原明
  • Organizer: 第85回日本内分泌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-04-20
• [Presentation] 高血糖刺激によるアルドステロン合成酵素(CYP11B2)の発現増強効果 (2012)
  • Author(s): 16. 松田謙、伊藤貴子、宇留野晃、中村美輝、高橋朗、吉川雄朗、清水恭子、箱田明子、工藤正孝、佐藤文俊、伊藤貞嘉、菅原明
  • Organizer: 第85回日本内分泌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-04-20
• [Remarks]
  • URL: http://www.dmbc.med.tohoku.ac.jp/
• [Patent(Industrial Property Rights)] Nrf2活性化のバイオマーカー (2013)
  • Inventor(s): 山本雅之、宇留野晃、古津祐樹
  • Industrial Property Rights Holder: 国立大学法人東北大学 持田製薬株式会社
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-112877
  • Filing Date: 2013-05-29
• [Patent(Industrial Property Rights)] Nrf2活性化のバイオマーカー (2013)
  • Inventor(s): 山本雅之、宇留野晃、古澤祐樹
  • Industrial Property Rights Holder: 東北大学、持田製薬株式会社
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-112877
  • Filing Date: 2013-05-29