Identification of molecular mechanisms for AQP2 activation to deveplop its inhibitor

• Project/Area Number: 15K09286
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: YUI Naofumi 東京医科歯科大学, 大学院医歯学総合研究科, 非常勤講師 (00633976)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 水チャネル / リン酸化 / 脱リン酸化 / 細胞内輸送 / 集合管 / バソプレシン / アクアポリン2 / 尿崩症 / アクアポリン２ / 心不全

Outline of Final Research Achievements

In this study, we developed a phospho-specific AQP2 immuno-isolation technique, and identified that vasopressin-mediated AQP2 Ser-261 phospho-regulation is processing in combination with Ser-256 and Ser-269 phosphorylation. pS256-pS261-AQP2 is phophorylated at Ser-269 to be pS256-pS261-pS269 triplly phospho-form, and then dephosphorylated at Ser-261 to be transformed into pS256-pS269-AQP2. We further revealed that the subsequent Ser-261 dephosphorylation was required to be accumulated in apical plasma membrane in concert with prior Ser-256 and Ser-269 phosphorylation.

Research Products

• [Int'l Joint Research] Massachusetts General Hospital(米国)
• [Journal Article] AKAPs-PKA disruptors increase AQP2 activity independently of vasopressin in a model of nephrogenic diabetes insipidus (2018)
  • Author(s): Ando Fumiaki、Mori Shuichi、Yui Naofumi、Morimoto Tetsuji、Nomura Naohiro、Sohara Eisei、Rai Tatemitsu、Sasaki Sei、Kondo Yoshiaki、Kagechika Hiroyuki、Uchida Shinichi
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 1411-1411
  • DOI: 10.1038/s41467-018-03771-2
  • Peer Reviewed / Open Access
• [Journal Article] The proteasome inhibitor bortezomib attenuates renalfibrosis in mice via supression of TGF b1 (2018)
  • Author(s): Zeniya M, Mori T, Yui N, Nomura N, Mandai S, Isobe K, Chiga M, Sohara E, Rai T, Uchida S.
  • Journal Title: Scientific Reports Volume: 7 Pages: 13086-13086
  • Peer Reviewed / Open Access
• [Journal Article] Ser-261 phospho-regulation is involved in pS256 and pS269-mediated apical translocation. (2017)
  • Author(s): Yui N, Ando F, Sasaki S, Uchida S.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 490 Pages: 1039-1039
  • Peer Reviewed
• [Journal Article] Ezrin directly interacts with AQP2 and promotes its endocytosis. (2017)
  • Author(s): Li W, Jin WW, Tsuji K, Chen Y, Nomura N, Su L, Yui N, Arthur J, Cotecchia S, Paunescu TG, Brown D, Lu HAJ.
  • Journal Title: Journal of Cell Science Volume: 130 Pages: 2914-2914
• [Journal Article] Aquaporin-2 Ser-261 phosphorylation is regulated in combination with Ser-256 and Ser-269 phosphorylation (2017)
  • Author(s): Naofumi Yui, Sei Sasaki, Shinichi Uchida
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 482 Issue: 4 Pages: 524-529
  • DOI: 10.1016/j.bbrc.2016.11.118
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Wnt5a induces renal AQP2 expression by activating calcineurin signalling pathway. (2016)
  • Author(s): Ando F, Sohara E, Morimoto T, Yui N, Nomura N, Kikuchi E, Takahashi D, Mori T, Vandewalle A, Rai T, Sasaki S, Kondo Y, Uchida S.
  • Journal Title: Nat Commun. Volume: 7 Issue: 1 Pages: 13636-13636
  • DOI: 10.1038/ncomms13636
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Bence-Jones Protein λ-type Multiple Myeloma Patient Withdrawn from Maintenance Hemodialysis after Long-term Bortezomib and Dexamethasone Therapy (2016)
  • Author(s): Wakaba Yamaguchi, Naofumi Yui, Toshikage Nagao, Gaku Oshikawa, Mariko Negi, Soichiro Iimori, Tomokazu Okado, Tatemitsu Rai, Shinichi Uchida.
  • Journal Title: Internal Medicine Volume: 55 Issue: 3 Pages: 263-268
  • DOI: 10.2169/internalmedicine.55.5310
  • NAID: 130005122595
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Retroperitoneal Fibrosis in Chronic Kidney Disease (2015)
  • Author(s): Yuki Yoshizaki, Naofumi Yui, Tomokazu Okado, Junichi Ishigami, Soichiro Iimori, Katsuyuki Oi, Eisei Sohara, Sei Sasaki, Tatemitsu Rai, Shinichi Uchida.
  • Journal Title: General Medicine Volume: 16 Issue: 2 Pages: 103-106
  • DOI: 10.14442/general.16.103
  • NAID: 130005078484
  • Peer Reviewed / Open Access
• [Journal Article] Anemia mmanegement and morality risk in newly visiting patients with chronic kidney disease in Japan: The CKD-ROUTE study. (2015)
  • Author(s): Soichiro Iimori, Shotaro Naito, Yumi Noda, Hidenori Nishida, Naofumi Yui, Tomokazu Okado, Sei Sasaki, Shinichi Uchida, Tatemitsu Rai.
  • Journal Title: Nephrology Volume: 20 Issue: 9 Pages: 601-608
  • DOI: 10.1111/nep.12493
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] アクアポリン2の細胞内輸送調節における複合的リン酸化制御機構の解明 (2017)
  • Author(s): 油井直史、佐々木成、内田信一
  • Organizer: 日本腎臓学会
• [Presentation] Quantification of singleand multi-site AQP2 phosphorylation (2017)
  • Author(s): Yui N, Uchida S.
  • Organizer: 51th Annual Meeting of American Society of Nephrology
  • Int'l Joint Research
• [Presentation] 新規腎臓線維化改善薬としてのbortezomibの検討 (2017)
  • Author(s): 銭谷慕子、森崇寧、油井直史、野村尚弘、千賀宗子、高橋大栄、蘇原映誠、頼建光、内田信一
  • Organizer: 日本腎臓学会
• [Presentation] Regulated Ser-261 dephosphorylation combined with Ser-256 and Ser-269 phosphorylation in the C-terminus of aquaporin-2 water channel (2016)
  • Author(s): Naofumi Yui, Sei Sasaki, Shinichi Uchida
  • Organizer: 50th Annual Meeting of American Society of Nephrology
  • Place of Presentation: Chicago, USA
  • Year and Date: 2016-11-15
  • Int'l Joint Research
• [Presentation] The proteasome inhibitor bortezomib attenuate renal fibrosis in mice (2016)
  • Author(s): Moko Zeniya, Takayasu Mori, Naohiro Nomura, Naofumi Yui, Eisei Sohara, Tatemitsu Rai, Shinichi Uchida
  • Organizer: 50th Annual Meeting of American Society of Nephrology
  • Place of Presentation: Chicago, USA
  • Year and Date: 2016-11-15
  • Int'l Joint Research
• [Presentation] カルシニューリンは腎性尿崩症治療の標的分子である (2016)
  • Author(s): 安藤史顕、蘇原映誠、油井直史、野村尚弘、菊池絵梨子、高橋大栄、森崇寧、頼建光、佐々木成、内田信一
  • Organizer: 第59回日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜 横浜 神奈川
  • Year and Date: 2016-06-17
• [Presentation] Dephosphorylation at Ser-261 is a determinant for the regulated AQP2 apical accumulation (2015)
  • Author(s): Naofumi Yui, Sei Sasaki, Shinichi Uchida
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Diego, USA
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Sunitinib-induced nephrotic syndrome and acute kidney injury in a malignant insulinoma patient: a case report (2015)
  • Author(s): Shoda Wakana, Naofumi Yui, Shotaro Naito, Soichiro Iimori, Koichiro Susa, Takayasu Mori, Naohiro Nomura, Eisei Sohara, Tomokazu Okado, Tatemitsu Rai, Shinichi Uchida.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Diego, USA
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] スニチニブによる腎症の一例 (2015)
  • Author(s): 正田若菜、油井直史、工藤篤、大橋敦希、井上祐一、飯盛聡一郎、須佐紘一郎、森崇寧、佐藤文絵、野村尚弘、桑名仁、内藤省太郎、蘇原映誠、岡戸丈和、頼建光、内田信一
  • Organizer: 日本腎臓学会東部学術大会
  • Place of Presentation: 東京ミッドタウン ホール＆カンファレンス（東京都港区）
  • Year and Date: 2015-10-02
• [Presentation] バソプレッシン刺激によるアクアポリン２の活性化はGABAb受容体情報伝達機構により調節を受ける (2015)
  • Author(s): 谷田部淳一、高野梢、谷田部緑、油井直史、蘇原映誠、内田信一、渡辺毅、木村純子
  • Organizer: 日本腎臓学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-06-07
• [Presentation] Ser-269リン酸化AQP2の細胞内局在の時系列変化 (2015)
  • Author(s): 油井直史、佐々木成、内田信一
  • Organizer: 日本腎臓学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-06-06
• [Remarks] 東京医科歯科大学腎臓内科
  • URL: http://www.tmd.ac.jp/grad/kid/
• [Remarks] 東京医科歯科大学 腎臓内科学
  • URL: http://www.tmd.ac.jp/grad/kid/kid-J.htm