網膜疾患における受容体随伴プロレニン系と断片別（プロ）レニン受容体の機能解析

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24791823
• Research Institution: Hokkaido University
• Principal Investigator: 神田 敦宏 北海道大学, 医学(系)研究科(研究院), 特任講師 (80342707)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: (プロ)レニン受容体 / プロレニン / レニン・アンジオテンシン 系 / 血管新生 / 網膜疾患

Outline of Annual Research Achievements

老化や生活習慣による炎症・血管新生が原因で引き起こされる網膜疾患[加齢黄斑変性(AMD)や糖尿病網膜症(PDR )など]の罹患者数 が近年急増している。申請者らのグループは、レニン-アンジオテンシン系(RAS)と受容体随伴プロレニン系(RAPS)がそれら網膜疾患に おいて重要な役割を担っていることを明らかにした。本研究では、組織発生や疾患における分子病態を制御し、RAPSの鍵分子である(プロ)レニン受容体の詳細な生理機能解析をはじめとして、生活習慣病発症におけるRAPSおよび機能断片別(P)RRの関与をヒト 正常・病態組織やトランスジェニックマウスなど用いて詳細に明らかする。
本年度は、成体マウス網膜における(プロ)レニン受容体共役タンパク質を同定するため、抗(プロ)レニン受容体抗体を用いた免疫沈降/質量分析解析(IP/MS)を行った。さらに免疫染色法などによりIP/MS結果を検証し、siRNAによる(プロ)レニン受容体ノックダウンを行い共役タンパク質の機能を解析した。（(プロ)レニン受容体は、解糖系における酵素の一つ、ピルビン酸デヒドロゲナーゼE1βサブユニット（PDHB）と共役することを同定し、さらにsiRNAによる(プロ)レニン受容体遺伝子ノックダウンは、細胞内のPDH活性やアセチル-CoAレベルを減少、一方、乳酸レベルの上昇が認められた。これらのことより、(プロ)レニン受容体は糖代謝経路に関与していると示唆された。
また、結膜節外辺縁帯B細胞性リンパ腫の線維化・転移に，組織レニン・アンジオテンシン系が関与し，さらにその上流に位置する(プロ)レニン受容体が重要な鍵分子であることを，ヒト組織において初めて明らかにした。

Research Products

• [Journal Article] ATP6AP2/(pro)renin receptor contributes to glucose metabolism via stabilizing the pyruvate dehydrogenase E1 b-subunit. (2015)
  • Author(s): Kanda A, Noda K, Ishida S.
  • Journal Title: J Biol Chem. Volume: 290 Pages: 9690-9700
  • DOI: 10.1074/jbc.M114.626713.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Involvement of the Receptor-Associated Prorenin System in the Pathogenesis of Human Conjunctival Lymphoma. (2015)
  • Author(s): Ishizuka ET, Kanda A, Kase S, Noda K, Ishida S.
  • Journal Title: Invest Ophthalmol Vis Sci. Volume: 56 Pages: 74-80
  • DOI: 10.1167/iovs.14-15743.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Genistein Attenuates Choroidal Neovascularization. (2014)
  • Author(s): Kinoshita S, Noda K, Tagawa Y, Inafuku S, Dong Y, Fukuhara J, Dong Z, Ando R, Kanda A, Ishida S.
  • Journal Title: J Nutr Biochem. Volume: 25 Pages: 1177-1182
  • DOI: 10.1016/j.jnutbio.2014.06.004.
  • Peer Reviewed
• [Journal Article] A comparison of N-glycan profiles in human plasma and vitreous fluid. (2014)
  • Author(s): Inafuku S, Noda K, Amano M, Ohashi, Yoshizawa C, Saito W, Kanda A, Nishimura S, Ishida S.
  • Journal Title: Graefes Arch Clin Exp Ophthalmol. Volume: 252 Pages: 1235-1243
  • DOI: 10.1007/s00417-014-2671-x.
  • Peer Reviewed
• [Journal Article] Amelioration of experimental autoimmune uveoretinitis by inhibition of glyceraldehyde derived-advanced glycation end product formation. (2014)
  • Author(s): Dong Z, Iwata D, Kitaichi N, Takeuchi M, Sato M, Endo N, Iwabuchi K, Ando R, Fukuhara J, Kinoshita S, Lennikov A, Kitamura M, Mizuuchi K, Kanda A, Noda K, Namba K, Yamagishi S, Ohno S, Ishida S.
  • Journal Title: J Leukoc Biol. Volume: 96 Pages: 1077-1085
  • DOI: 10.1189/jlb.3A0513-288RRR.
  • Peer Reviewed
• [Journal Article] Decreased Proteasomal Activity Causes Photoreceptor Degeneration in Mice. (2014)
  • Author(s): Ando R, Noda K, Tomaru U, Kamoshita M, Ozawa Y, Notomi S, Hisatomi T, Noda M, Kanda A, Ishibashi T, Kasahara M, Ishida S.
  • Journal Title: Invest Ophthalmol Vis Sci. Volume: 55 Pages: 4682-4690
  • DOI: 10.1167/iovs.13-13272.
  • Peer Reviewed
• [Journal Article] Aqueous humor levels of placental growth factor in diabetic retinopathy. (2014)
  • Author(s): Ando R, Noda K, Namba S, Saito W, Kanda A, Ishida S.
  • Journal Title: Acta Ophthalmol. Volume: 92 Pages: 245-246
  • DOI: 10.1111/aos.12251.
  • Peer Reviewed
• [Journal Article] A case of paraneoplastic optic neuropathy and outer retinitis positive for autoantibodies against collapsin response mediator protein-5, recoverin, and α-enolase. (2014)
  • Author(s): Saito M, Saito W, Kanda A, Ohguro H, Ishida S.
  • Journal Title: BMC Ophthalmol. Volume: 14 Pages: 5-5
  • DOI: 10.1186/1471-2415-14-5.
  • Peer Reviewed
• [Journal Article] Expression of vascular endothelial growth factor in human ocular adnexal lymphoma. (2014)
  • Author(s): Kinoshita S, Kase S, Ando R, Dong Z, Fukuhara J, Dong Y, Takashina S, Noda K, Noda M, Kanda A, Ishida S.
  • Journal Title: Invest Ophthalmol Vis Sci. Volume: 55 Pages: 3461-3467
  • DOI: 10.1167/iovs.13-13510.
  • Peer Reviewed
• [Journal Article] 増殖糖尿病網膜症の病態形成における（プロ）レニン受容体. (2014)
  • Author(s): 神田敦宏
  • Journal Title: 日本眼科学会雑誌 Volume: 118 Pages: 916-926
  • Peer Reviewed
• [Journal Article] 糖尿病網膜症とRAS (2014)
  • Author(s): 神田敦宏、石田 晋
  • Journal Title: Angiotensin Research Volume: 11 Pages: 190-193
  • Peer Reviewed
• [Presentation] Identification of (pro)renin receptor/Atp6ap2-binding proteins in the retina of adult mice. (2015)
  • Author(s): Kanda A, Noda K, Ishida S.
  • Organizer: Association for Research in Vision and Ophthalmology
  • Place of Presentation: Florida, USA
  • Year and Date: 2015-05-04 – 2015-05-08
• [Presentation] （プロ）レニン受容体と糖代謝 (2015)
  • Author(s): 神田敦宏
  • Organizer: 第7回（プロ）レニン受容体フォーラム
  • Place of Presentation: 熊本大学（熊本県、熊本市）
  • Year and Date: 2015-03-21 – 2015-03-21
• [Presentation] ATP6AP2/(pro)renin receptor contributes to glucose metabolism via stabilizing the E1 β subunit of pyruvate dehydrogenase complex. (2015)
  • Author(s): Kanda A, Noda K, Ishida S.
  • Organizer: Asia-ARVO 2015
  • Place of Presentation: Pacifico Yokohama(Kanagawa, Yokohama）
  • Year and Date: 2015-02-16 – 2015-02-19
• [Presentation] Atp6ap2/(pro)renin receptor is associated with cell polarity required for laminar formation during retinal development in mice. (2015)
  • Author(s): Kanda A.
  • Organizer: Asia-ARVO 2015
  • Place of Presentation: Pacifico Yokohama(Kanagawa, Yokohama）
  • Year and Date: 2015-02-16 – 2015-02-19
  • Invited
• [Presentation] Atp6ap2/(pro)renin receptor is associated with cell polarity required for laminar formation during retinal development in mouse. (2015)
  • Author(s): Kanda A.
  • Organizer: 2015 Meeting with Hokkaido University & Chang Gung Memorial Hospitals
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2015-01-31 – 2015-01-31
• [Presentation] Atp6ap2/(pro)renin receptor is associated with cell polarity required for laminar formation during retinal development in mouse. (2014)
  • Author(s): Kanda A
  • Organizer: 9th Japan-Korea International Symposium in Ophthalmology
  • Place of Presentation: Hokkaido University（Hokkaido, Sapporo)
  • Year and Date: 2014-12-01 – 2014-12-01
• [Presentation] 網膜におけるレニン・アンジオテンシン系 (2014)
  • Author(s): 神田敦宏
  • Organizer: 第1回眼科基礎研究の会
  • Place of Presentation: ホテル三浦華園（北海道、滝川市）
  • Year and Date: 2014-08-23 – 2014-08-23
• [Presentation] Atp6ap2/(pro)renin receptor interacts with Par3 as a cell polarity determinant required for laminar formation during retinal development in mice. (2014)
  • Author(s): Kanda A, Yuki K, Furukawa T, Ichihara A, Ishida S.
  • Organizer: World Ophthalmology Congress 2014 Tokyo
  • Place of Presentation: Tokyo International Forum（Tokyo, Chiyoda)
  • Year and Date: 2014-04-02 – 2014-04-04
• [Presentation] (Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy (2014)
  • Author(s): 神田敦宏
  • Organizer: 第118回日本眼科学会総会
  • Place of Presentation: 東京国際フォーラム（東京都、千代田区）
  • Year and Date: 2014-04-02 – 2014-04-04
• [Book] Roles of the retinal pigment epithelium in neuroprotection. Neuroprotection and Regeneration for Retinal Diseases. (2014)
  • Author(s): Kanda A, Ishida S.
  • Total Pages: 341
  • Publisher: Springer.