Significance of WNK1 as a master regulator of renal proximal sodium transport

• Project/Area Number: 16K09640
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: The University of Tokyo
• Principal Investigator: Horita Shoko 東京大学, 医学部附属病院, 助教 (20534895)
• Co-Investigator(Kenkyū-buntansha): 中村 元信 東京大学, 医学部附属病院, 助教 (40459524) ; 山崎 修 帝京大学, 医学部, 講師 (80757229) ; 鈴木 正志 東京学芸大学, 保健管理センター, 教授 (90595662)
• Research Collaborator: Ando Hideaki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 近位尿細管 / ナトリウム輸送 / 高血圧 / 心不全 / WNK1 / OSR1/SPAK / NBCe1 / siRNA / ナトリウム再吸収 / WNK / Na輸送

Outline of Final Research Achievements

In renal proximal tubules (PTs) insulin (Ins) stimulates both apical NHE3 and basolateral NBCe1 via PI3K/Akt signaling, so does thiazolidinedione (TZD) via PPARg/ERK signaling; also AngII via NO/ERK signaling in human. However, the coordination mechanism regulating PT Na transport was poorly understood. We studied the role of WNK1/OSR1 pathway.
In freshly-isolated rat and human PTs, Ins and TZD markedly stimulated both NHE3 and NBCe1 activities, which was totally suppressed by OSR1/SPAK inhibitor, Closantel. Closantel also totally suppressed the AngII-stimulated NBCe1 and NHE3 activities in human PTs. Immunostaining confirmed these results. In overnight incubated rat PTs, siRNA against WNK1 but not WNK3 abolished the stimulatory effects of TZD and ins on NBCe1, so did siRNA against OSR1 but not SPAK.
These results indicate, for the first time, that in PTs signaling cascades stimulating Na transport converge into WNK1/OSR1 pathway, which may work as a master regulator of PT Na transport.

Academic Significance and Societal Importance of the Research Achievements

本研究にて，これまで不明であった近位尿細管Na輸送の異なる刺激要素（インスリン，チアゾリジン，アンジオテンシンII）を，WNK1/OSR1が収斂し，WNK1/OSR1がこの輸送のmaster regulatorであることが初めて示された。すなわち，Na過剰貯留による高血圧，心不全等の治療のターゲットにWNK1/OSR1がなりえることが示唆され，新規治療薬開発においても有力な候補となることが期待される。

Research Products

• [Journal Article] A Patient with MPO-ANCA-positive IgA Nephropathy Diagnosed with the Clinical Onset of Macrohematuria (2019)
  • Author(s): Yasukawa Minoru、Kitagawa Sachiko、Togashi Ryo、Asakawa Shinichiro、Nagura Michito、Arai Shigeyuki、Yamazaki Osamu、Tamura Yoshifuru、Kondo Fukuo、Ohashi Ryuji、Uchida Shunya、Shibata Shigeru、Fujigaki Yoshihide
  • Journal Title: Internal Medicine Volume: 58 Issue: 14 Pages: 2051-2056
  • DOI: 10.2169/internalmedicine.2475-18
  • NAID: 130007679526
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-07-15
  • Peer Reviewed / Open Access
• [Journal Article] A Case of Rheumatoid Arthritis Presenting with Renal Thrombotic Microangiopathy Probably due to a Combination of Chronic Tacrolimus Arteriolopathy and Severe Hypertension (2019)
  • Author(s): Honma Fumika、Fujigaki Yoshihide、Nemoto Yoshikazu、Kikuchi Hirotoshi、Nagura Michito、Arai Shigeyuki、Ishizawa Kenichi、Yamazaki Osamu、Tamura Yoshifuru、Kondo Fukuo、Ohashi Ryuji、Uchida Shunya、Shibata Shigeru
  • Journal Title: Case Reports in Nephrology Volume: 2019 Pages: 1-7
  • DOI: 10.1155/2019/3923190
  • Peer Reviewed / Open Access
• [Journal Article] Phosphate binding by sucroferric oxyhydroxide ameliorates renal injury in the remnant kidney model (2019)
  • Author(s): Yoshikazu Nemoto, Takanori Kumagai, Kenichi Ishizawa, Yutaka Miura, Takeshi Shiraishi, Chikayuki Morimoto, Kazuhiro Sakai, Hiroki Omizo, Osamu Yamazaki, Yoshifuru Tamura, Yoshihide Fujigaki, Hiroshi Kawachi, Makoto Kuro-o Makoto, Shunya Uchida, Shigeru Shibata
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 1732-1732
  • DOI: 10.1038/s41598-018-38389-3
  • Peer Reviewed / Open Access
• [Journal Article] SLC4A4 compound heterozygous mutations in exon?intron boundary regions presenting with severe proximal renal tubular acidosis and extrarenal symptoms coexisting with Turner’s syndrome: a case report (2018)
  • Author(s): Horita Shoko、Simsek Enver、Simsek Tulay、Yildirim Nilgun、Ishiura Hiroyuki、Nakamura Motonobu、Satoh Nobuhiko、Suzuki Atsushi、Tsukada Hiroyuki、Mizuno Tomohito、Seki George、Tsuji Shoji、Nangaku Masaomi
  • Journal Title: BMC Medical Genetics Volume: 19 Issue: 1 Pages: 103-111
  • DOI: 10.1186/s12881-018-0612-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 尿細管性アシドーシスの発症機序は? 基底側輸送体・管腔側プロトンポンプの機能不全が平衡式反応を低下させ、近位・遠位尿細管性アシドーシスへ進展させる(Q&A) (2018)
  • Author(s): 堀田 晶子
  • Journal Title: 日本医事新報 Volume: 4907 Pages: 58-59
• [Journal Article] Effects of Nitric Oxide on Renal Proximal Tubular Na+ Transport. (2017)
  • Author(s): Satoh N, Nakamura M, Suzuki A, Tsukada H, Horita S, Suzuki M, Moriya K, Seki G.
  • Journal Title: Biomed Res Int. Volume: 2017 Pages: 6871081-6871089
  • DOI: 10.1155/2017/6871081
  • Peer Reviewed / Open Access
• [Journal Article] The role of renal proximal tubule transport in the regulation of blood pressure (2017)
  • Author(s): Shoko Horita1, Motonobu Nakamura, Masashi Suzuki, Nobuhiko Satoh, Atsushi Suzuki, Yukio Homma, Masaomi Nangaku
  • Journal Title: Kidney Research and Clinical Practice Volume: 36 Issue: 1 Pages: 12-21
  • DOI: 10.23876/j.krcp.2017.36.1.12
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Functional coupling of V-ATPase and CLC-5. (2017)
  • Author(s): Satoh N, Suzuki M, Nakamura M, Suzuki A, Horita S, Seki G, Moriya .
  • Journal Title: World Journal of Nephrology Volume: 6 Issue: 1 Pages: 14-20
  • DOI: 10.5527/wjn.v6.i1.14
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] インスリン抵抗性とインスリン腎尿細管ナトリウム輸送作用 (2017)
  • Author(s): 中村 元信, 鈴木 正志, 佐藤 信彦, 鈴木 淳司, 堀田 晶子, 南学 正臣
  • Journal Title: 腎と透析 Volume: 82巻2号 Pages: 280-286
  • Peer Reviewed
• [Journal Article] 【骨ミネラル代謝と疾患】代謝性アシドーシスと骨代謝のクロストーク (2017)
  • Author(s): 堀田 晶子, 佐藤 信彦, 中村 元信
  • Journal Title: 腎と骨代謝 Volume: 30巻1号 Pages: 53-61
  • Open Access
• [Journal Article] Selective Insulin Resistance in the Kidney. (2016)
  • Author(s): Horita S, Nakamura M, Suzuki M, Satoh N, Suzuki A, Seki G.
  • Journal Title: Biomed Res Int Volume: 2016 Pages: 1-8
  • DOI: 10.1155/2016/5825170
  • Peer Reviewed / Open Access
• [Journal Article] A pure chloride channel mutant of CLC-5 causes Dent’s disease via insufficient V-ATPase activation (2016)
  • Author(s): Nobuhiko Satoh, Hideomi Yamada, Osamu Yamazaki, Masashi Suzuki, Motonobu Nakamura, Atsushi Suzuki, Akira Ashida, Daisuke Yamamoto, Yoshitsugu Kaku, Takashi Sekine, George Seki, Shoko Horita
  • Journal Title: Pfluegers Aｒch Volume: 印刷中 Issue: 7 Pages: 1183-96
  • DOI: 10.1007/s00424-016-1808-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] EFFECTS OF PARATHYROID HORMONE ON GLUCOSE METABOLISM IN RENAL PROXIMAL TUBULES (2019)
  • Author(s): H. Tsukada, M. Nakamura, N. Satoh, T. Mizuno, Y. Sato, S. Horita, G. Seki, H. Kume, M. Nangaku, M. Suzuki
  • Organizer: ISN World Congress of Nephrology 2019, Merbourne, Australia
  • Int'l Joint Research
• [Presentation] Roles of Na+/HCO3- cotransporter NBCn2 in acid-base transport in the apical membrane of renal proximal tubules (2019)
  • Author(s): M. NAKAMURA, A. Suzuki, S. Horita, N. Satoh, H. Tsukada, Y. Sato, G. Seki, H. Kume, M. Nangaku, M. Suzuki
  • Organizer: ISN World Congress of Nephrology 2019, Merbourne, Australia
  • Int'l Joint Research
• [Presentation] A Pivotal Role of WNK1/OSR1 Pathway in Regulation of Renal Proximal Sodium Transport (2018)
  • Author(s): Motonobu Nakamura, Shoko Horita, Nobuhiko Satoh, George Seki, Tomohito Mizuno, Hiroyuki Tsukada, Yusuke Sato, Haruki Kume, Masaomi Nangaku, Masashi Suzuki
  • Organizer: ASN kidney Week 2018, San Diego, USA
  • Int'l Joint Research
• [Presentation] Sucroferric Oxyhydroxide Ameliorates Glomerular Podocyte and Tubulointerstitial Injury in the Rat Remnant Kidney Model (2018)
  • Author(s): Yoshikazu Nemoto, Takanori Kumagai, Takeshi Shiraishi, Kenichi Ishizawa, Osamu Yamazaki, Yoshifuru Tamura, Makoto Kuro-o, Shunya Uchida, Shigeru Shibata
  • Organizer: ASN kidney Week 2018, San Diego, USA
  • Int'l Joint Research
• [Presentation] Urinary Exosome Analysis in a Case of Licorice-Induced Pseudoaldosteronism (2018)
  • Author(s): Shinichiro Asakawa, Osamu Yamazaki, Yuto Hayama, Masaki Yamanaka, Emiko Kuribayashi-Okuma, Yoshihide Fujigaki, Shigeru Shibata
  • Organizer: ASN kidney Week 2018, San Diego, USA
  • Int'l Joint Research
• [Presentation] A Novel I551F Mutant of Na+/HCO3- Cotransporter NBCe1 Has Cytosolic Retention and Diminishes Transport Activity (2018)
  • Author(s): Osamu Yamazaki, Maho Yamashita, Jinping Li, Tadashi Yoshida, Junichi Hirahashi, Shigeru Shibata, Matsuhiko Hayashi
  • Organizer: ASN kidney Week 2018, San Diego, USA
  • Int'l Joint Research
• [Presentation] 副甲状腺ホルモンは近位尿細管ナトリウム輸送と糖新生に関与している (2018)
  • Author(s): 塚田 弘之, 佐藤 信彦, 中村 元信, 水野 智仁, 佐藤 悠佑, 堀田 晶子, 関 常司, 鈴木 正志, 久米 春喜, 南学 正臣
  • Organizer: 第61回日本腎臓学会学術総会
• [Presentation] 近位尿細管ナトリウム輸送調節におけるWNK1/OSR1経路の意義 (2018)
  • Author(s): 中村 元信, 佐藤 信彦, 塚田 弘之, 水野 智仁, 佐藤 悠佑, 堀田 晶子, 関 常司, 鈴木 正志, 久米 春喜, 南学 正臣
  • Organizer: 第61回日本腎臓学会学術総会
• [Presentation] VAIVT後のVascular Access開存における抗血小板薬の有用性 (2018)
  • Author(s): 水野 智仁, 中村 元信, 佐藤 信彦, 塚田 弘之, 一色 玲, 松本 明彦, 濱崎 敬文, 久米 春喜, 南学 正臣
  • Organizer: 第63回日本透析医学会学術集会・総会
• [Presentation] ナトリウム重炭酸共輸送体NBCe1の新規変異体I551Fはcytosolic retentionおよび機能低下を示す (2018)
  • Author(s): 山崎修
  • Organizer: 第9回分子腎臓フォーラム
• [Presentation] A novel case of SLC4A4 compound heterozygous mutationsins exon-intron boundary regions presenting with severe proximal renal tubular acidosis and extrarenal symptoms (2018)
  • Author(s): Horita S, Simsek E, Simsek T, Ishiura H, Nakamura M, Satoh N, Seki G, Tsuji S, Nangaku M
  • Organizer: ISN frontiers meeting 2018 Tokyo
  • Int'l Joint Research
• [Presentation] Stimulation of proximal tubule sodium transport by insulin is mediated via Akt2/mTORC2 pathway (2018)
  • Author(s): Nakamura M, Suzuki M, Satoh N, Tsukada H, Mizuno T, Sato Y, Horita S, Seki G, Kume H, Nangaku M.
  • Organizer: ISN frontiers meeting 2018 Tokyo
  • Int'l Joint Research
• [Presentation] 近位尿細管管腔側Na依存性酸塩基輸送体の検討 (2017)
  • Author(s): 鈴木 淳司,鈴木 正志,中村 元信,佐藤 信彦,関 常司,佐藤 悠佑,本間 之夫,堀田 晶子,南学 正臣
  • Organizer: 日本腎臓学会第60回学術総会
• [Presentation] インスリンはIRS1/Akt2/mTORCを介して近位尿細管糖新生を抑制する (2017)
  • Author(s): 中村 元信,鈴木 正志,佐藤 信彦,鈴木 淳司,塚田 弘之,関 常司,佐藤 悠佑,本間 之夫,堀田 晶子,南学 正臣
  • Organizer: 日本腎臓学会第60回学術総会
• [Presentation] 近位尿細管ナトリウム輸送調節におけるWNK1/OSR1/SPAKの意義 (2017)
  • Author(s): 中村 元信, 鈴木 正志,佐藤 信彦,鈴木 淳司,塚田 弘之,関 常司,佐藤 悠佑,本間 之夫,堀田 晶子,南学 正臣
  • Organizer: 日本腎臓学会第60回学術総会
• [Presentation] Insulin Suppresses Gluconeogenesis in Renal Proximal Tubules via the IRS1/Akt2/mTORC Pathway (2017)
  • Author(s): Nakamura M, Suzuki M, Satoh N, Suzuki A, Tsukada H, Seki G, Sato Y, Homma Y, Horita S, Nangaku M.
  • Organizer: American Society of Nephrology Kidney Week 2017
  • Int'l Joint Research
• [Presentation] Regulation of Blood Pressure by Renal Proximal Tubule Transport (2016)
  • Author(s): Shoko Horita
  • Organizer: The 36th Annual Meeting of the Korean Society of Nephrology
  • Place of Presentation: Grand Hilton Hotel, Seoul,Korea
  • Int'l Joint Research / Invited
• [Presentation] OHVIRA(obstructed hemivagina and ipsilateral renal anomary)症候群にIgA腎症を合併した症例 (2016)
  • Author(s): 堀田 晶子, 那須 かほり, 本田 謙次郎, 中村 元信, 川上 貴久, 林 玲匡, 新谷 裕加子, 高橋 さゆり, 本間 之夫, 藤乗 嗣泰, 南学 正臣
  • Organizer: 第46回日本腎臓学会東部学術大会
  • Place of Presentation: 東京 京王プラザホテル
• [Presentation] 尿細管性アシドーシスの進歩と課題 (2016)
  • Author(s): 関 常司, 佐藤 信彦, 中村 元信, 堀田 晶子, 鈴木 正志
  • Organizer: 第46回日本腎臓学会東部学術大会
  • Place of Presentation: 東京 京王プラザホテル
  • Invited
• [Presentation] インスリンによる近位尿細管Na再吸収亢進作用はAkt2とmTORC2を介している (2016)
  • Author(s): 中村 元信, 鈴木 正志, 佐藤 信彦, 鈴木 淳司, 関 常司, 久米 春喜, 本間 之夫, 堀田 晶子, 南学 正臣
  • Organizer: 第59回日本腎臓学会学術総会
  • Place of Presentation: 横浜 パシフィコ横浜
• [Presentation] 近位尿細管管腔側Na依存性酸塩基輸送機構の種差 (2016)
  • Author(s): 鈴木 淳司, 鈴木 正志, 中村 元信, 佐藤 信彦, 関 常司, 久米 春喜, 本間 之夫, 堀田 晶子, 南学 正臣
  • Organizer: 第59回日本腎臓学会学術総会
  • Place of Presentation: 横浜 パシフィコ横浜
• [Presentation] Insulin Stimulates Renal Proximal Tubule Sodium Transport via Akt2/ mTORC2 Pathway (2016)
  • Author(s): Motonobu Nakamura, Masashi Suzuki, Nobuhiko Satoh, George Seki, Atsushi Suzuki, Yusuke Sato, Yukio Homma, Shoko Horita, Masaomi Nangaku
  • Organizer: American Society of Nephrology Kidney Week 2016
  • Place of Presentation: Chicago, USA
• [Book] 【腎と透析】82巻2号：インスリン抵抗性とインスリン腎尿細管ナトリウム輸送作用 (2017)
  • Author(s): 中村 元信, 鈴木 正志, 佐藤 信彦, 鈴木 淳司, 堀田 晶子, 南学 正臣
  • Total Pages: 7
  • Publisher: (株)東京医学社
• [Book] 【腎と骨代謝】30巻1号：「代謝性アシドーシスと骨代謝のクロストーク」 (2017)
  • Author(s): 堀田 晶子, 佐藤 信彦, 中村 元信
  • Total Pages: 9
  • Publisher: 日本メディカルセンター