Physiological and pathophysiological significance of NBCn2 in luminal acid secretion in proximal tubules.

• Project/Area Number: 18K08201
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: The University of Tokyo (2020-2021); Tokyo Gakugei University (2018-2019)
• Principal Investigator: SUZUKI MASASHI 東京大学, 医学部附属病院, 届出研究員 (90595662)
• Co-Investigator(Kenkyū-buntansha): 堀田 晶子 東京大学, 医学部附属病院, 届出診療員 (20534895) ; 中村 元信 東京大学, 医学部附属病院, 助教 (40459524) ; 佐藤 信彦 東京大学, 医学部附属病院, 助教 (80572552) ; 山崎 修 帝京大学, 医学部, 講師 (80757229)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: NBCn2 / 近位尿細管 / 酸塩基平衡 / 腎臓内科学

Outline of Final Research Achievements

Sodium-dependent acid-base transport in the lumenal side of the proximal tubule has been questioned, although NHE3 is thought to be mainly responsible for sodium-dependent acid-base transport. In the present study, we analyzed acid-base transport in isolated proximal tubules and found that the NHE inhibitor EIPA suppressed acid-base transport by 10-50%, whereas DIDS suppressed it by 30-50% and simultaneous addition of EIPA and DIDS by more than 80%. siRNA against NBCn2 suppressed acid-base transport in the proximal tubular lumen by about 50%, and immunohistochemistry confirmed the expression of NBCn2. NBCn2 expression on the proximal tubular lumen may be involved in acid-base transport.

Academic Significance and Societal Importance of the Research Achievements

本研究では主にNa/H交換輸送体(NHE)3が司るとされてきた近位尿細管管腔側のナトリウム依存性酸塩基輸送がNHE3だけでなくNa-HCO3共輸送体NBCn2により行われていることを示すことができた。ナトリウムは血液中の主要な電解質であり、血圧のコントロールに重要な役割を果たしている。一方、近位尿細管は糸球体で濾過されたナトリウムの約80%を再吸収しており、今後血圧調節のメカニズム解明や新たな降圧剤開発に貢献できる可能性がある。

Research Products

• [Journal Article] Insulin promotes sodium transport but suppresses gluconeogenesis via distinct cellular pathways in?human and rat renal proximal tubules (2020)
  • Author(s): Nakamura Motonobu、Tsukada Hiroyuki、Seki George、Satoh Nobuhiko、Mizuno Tomohito、Fujii Wataru、Horita Shoko、Moriya Kyoji、Sato Yusuke、Kume Haruki、Nangaku Masaomi、Suzuki Masashi
  • Journal Title: Kidney International Volume: 97 Issue: 2 Pages: 316-326
  • DOI: 10.1016/j.kint.2019.08.021
  • Peer Reviewed / Open Access
• [Journal Article] Electrolyte transport in the renal collecting duct and its regulation by the renin?angiotensin?aldosterone system (2019)
  • Author(s): Yamazaki Osamu、Ishizawa Kenichi、Hirohama Daigoro、Fujita Toshiro、Shibata Shigeru
  • Journal Title: Clinical Science Volume: 133 Issue: 1 Pages: 75-82
  • DOI: 10.1042/cs20180194
  • Peer Reviewed
• [Journal Article] Calcineurin dephosphorylates Kelch-like 3, reversing phosphorylation by angiotensin II and regulating renal electrolyte handling (2019)
  • Author(s): Ishizawa Kenichi、Wang Qin、Li Jinping、Yamazaki Osamu、Tamura Yoshifuru、Fujigaki Yoshihide、Uchida Shunya、Lifton Richard P.、Shibata Shigeru
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 116 Issue: 8 Pages: 3155-3160
  • DOI: 10.1073/pnas.1817281116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Modulation of Cl- signaling and ion transport by recruitment of kinases and phosphatases mediated by the regulatory protein IRBIT (2018)
  • Author(s): Vachel Laura、Shcheynikov Nikolay、Yamazaki Osamu、Fremder Moran、Ohana Ehud、Son Aran、Shin Dong Min、Yamazaki-Nakazawa Ai、Yang Chin-Rang、Knepper Mark A.、Muallem Shmuel
  • Journal Title: Science Signaling Volume: 11 Issue: 554
  • DOI: 10.1126/scisignal.aat5018
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 副甲状腺ホルモンはPKC/FOXO1を介して近位尿細管糖新生を亢進させる (2019)
  • Author(s): 塚田 弘之、中村 元信、水野 智仁、佐藤 信彦、佐藤 悠佑、堀田 晶子、関 常司、久米 春喜、南学 正臣、鈴木 正志
  • Organizer: 第62回日本腎臓学会学術総会
• [Presentation] Parathyroid Hormone Enhances Gluconeogenesis via the PKC/FoxO1 Pathway in Proximal Tubules (2019)
  • Author(s): Hiroyuki Tsukada, Motonobu Nakamura, Shoko Horita, Wataru Fujii, Tomohito Mizuno, Nobuhiko Satoh, Yusuke Sato, George Seki, Haruki Kume, Masaomi Nangaku, Masashi Suzuki.
  • Organizer: Annual Meeting of The American Society of Nephrology
  • Int'l Joint Research
• [Presentation] Insulin Stimulates V-ATPase on Renal Proximal Tubules via the Akt/mTORC2 Pathway (2019)
  • Author(s): Motonobu Nakamura, Nobuhiko Satoh, Hiroyuki Tsukada, Tomohito Mizuno, Wataru Fujii, Shoko Horita, Masaomi Nangaku, Masashi Suzuki
  • Organizer: Annual Meeting of The American Society of Nephrology
  • 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): Nakamura, M, Suzuki, A, Horita, S, Satoh, N, Tsukada, H, Sato, Y, Seki, G, Kume, H, Nangaku, M, Suzuki, M
  • Organizer: ISN World Congress of Nephrology
  • Int'l Joint Research
• [Presentation] EFFECTS OF PARATHYROID HORMONE ON GLUCOSE METABOLISM IN RENAL PROXIMAL TUBULES (2019)
  • Author(s): Tsukada, H, Nakamura, M, Satoh, N, Mizuno, T, Sato, Y, Horita, S, Seki, G, Kume, H, Nangaku, M, Suzuki, M
  • Organizer: ISN World Congress of Nephrology
  • Int'l Joint Research
• [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] 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] A Pivotal Role of WNK1/OSR1 Pathway in Regulation of Renal Proximal (2018)
  • Author(s): Motonobu Nakamura, Shoko Horita, Nobuhiko Satoh, George Seki, Tomohito Mizuno, Hiroyuki Tsukada, Yusuke Sato, Haruki Kume, Masaomi Nangaku, Masashi Suzuki.
  • Organizer: Annual Meeting of The American Society of Nephrology
  • 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: Annual Meeting of The American Society of Nephrology
  • Int'l Joint Research