Stimulatory effect of V-ATPase of Insulin on proximal tubules

• Project/Area Number: 17K16071
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: The University of Tokyo
• Principal Investigator: Nakamura Motonobu 東京大学, 医学部附属病院, 助教 (40459524)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 酸塩基平衡 / インスリン / 近位尿細管 / 腎生理 / mTOR / mTORC2 / V-ATPase / mTORC / mTORC1 / NHE3 / 腎臓内科学 / 水電解質代謝学 / ナトリウム輸送 / エンドサイトーシス

Outline of Final Research Achievements

We found that V-ATPase activity on the luminal side of renal proximal tubules was activated by insulin by using a freshly isolated proximal tubule which was obtained from mouse kidney cortex. This stimulation by insulin was almost completely suppressed by Akt inhibitor (Akt inhibitor VIII) and mTORC1/2 inhibitor (PP242), but not by mTORC1 inhibitor (Rapamycin). These results indicated that the stimulation of V-ATPase activity on the luminal side of renal proximal tubules by insulin is mediated via Akt/mTORC2 pathway.

Academic Significance and Societal Importance of the Research Achievements

インスリンは近位尿細管管腔側におけるナトリウム輸送のみならず、酸塩基平衡の制御に関与していることが示された。このことから、高インスリン血症が酸血症に関与している可能性が示唆された。さらに、この制御にはmTORC2が関与していることが示唆された。mTORC2選択的な阻害剤は、腎疾患の創薬ターゲットになる可能性があると考えられる。

Research Products

• [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
• [Presentation] Stimulation of proximal tubule sodium transport by insulin is mediated via Akt2/mTORC2 pathway (2018)
  • Author(s): Motonobu Nakamura, Masashi Suzuki, Nobuhiko Satoh, Atsushi Suzuki, Hiroyuki Tsukada, George Seki, Yusuke Sato, Yukio Homma, Shoko Horita, Masaomi Nangaku
  • Organizer: International Society of Nephrology, Frontiers meeting 2018 Tokyo
  • Int'l Joint Research
• [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: International Society of Nephrology, Frontiers meeting 2018 Tokyo
• [Presentation] Insulin suppresses gluconeogenesis in renal proximal tubules via IRS1/Akt2/mTORC pathway. (2017)
  • Author(s): Motonobu Nakamura, Masashi Suzuki, Nobuhiko Satoh, Atsushi Suzuki, Hiroyuki Tsukada, George Seki, Yusuke Sato, Yukio Homma, Shoko Horita, Masaomi Nangaku
  • Organizer: Kidney Week 2017: American Society of Nephrology Annual Meeting Newolins, New Orleans U.S.A.
  • Int'l Joint Research
• [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 、仙台 日本
• [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 、仙台 日本