The roles of two isoforms of fructokinase on diabetic kidney disease

• Project/Area Number: 18K08238
• 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: Nagoya University
• Principal Investigator: ISHIMOTO TAKUJI 名古屋大学, 医学部附属病院, 講師 (00534835)
• Co-Investigator(Kenkyū-buntansha): 丸山 彰一 名古屋大学, 医学系研究科, 教授 (10362253)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: フルクトース代謝 / KHK-C KOマウス / 糖尿病性腎臓病 / アンチセンスオリゴ / CRISPR/Cas9 / マウスKHK-C強制発現細胞株 / フルクトース / ケトヘキソキナーゼ / フルクトキナーゼ

Outline of Final Research Achievements

Diabetic KHK-A KO mice developed severe renal injury compared to diabetic wild-type mice, and this was associated with further increases of intrarenal fructose, DHAP, TCA cycle intermediate levels, and severe inflammation. In contrast, those were prevented in diabetic KHK-A/C KO mice. Further, diabetic KHK-A KO mice demonstrated decreased renal NAD+ level. These results suggest that KHK-C might play a deleterious role in DKD progression through endogenous fructose metabolism, and that KHK-A plays a unique protective role against the development of DKD. In addition, in this study, KHK-C knockout mice were newly developed using CRISPR/cas9 system. Furthermore, to develop the molecular therapy targeting KHK-C, KHK-C specific antisense oligonucleotide was made.

Academic Significance and Societal Importance of the Research Achievements

本研究において検討を行った糖尿病性腎臓病（DKD）は現在も腎不全の原疾患の第一位であり、その治療法の確立が切望されている。また、先進国のみならず発展途上国も含めて世界中で増加しているメタボリック症候群および糖尿病の誘因の一つとして、砂糖・果糖ブドウ糖液糖に含まれるフルクトースの過量摂取が世界中で注目されている。本研究において分子標的としてのフルクトース代謝酵素KHKの有用性について、２種のアイソフォーム別に検討することは、DKDのおよびメタボリック症候群に対する有効性・選択性の高い治療法の開発につながると考えられる。

Research Products

• [Int'l Joint Research] University of Colorado Denver(米国)
• [Int'l Joint Research] Renal Diseases and Hypertension/University of Colorado Denver(米国)
• [Int'l Joint Research] Renal Diseases and Hypertension/University of Colorado Denver(米国)
• [Journal Article] Vasopressin mediates fructose-induced metabolic syndrome by activating the V1b receptor (2021)
  • Author(s): Andres-Hernando Ana、Jensen Thomas J.、Kuwabara Masanari、Orlicky David J.、Cicerchi Christina、Li Nanxing、Roncal-Jimenez Carlos A.、Garcia Gabriela E.、Ishimoto Takuji、Maclean Paul S.、Bjornstad Petter、Sanchez-Lozada Laura Gabriela、Kanbay Mehmet、Nakagawa Takahiko、Johnson Richard J.、Lanaspa Miguel A.
  • Journal Title: JCI Insight Volume: 6 Issue: 1
  • DOI: 10.1172/jci.insight.140848
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Fructose Increases the Activity of Sodium Hydrogen Exchanger in Renal Proximal Tubules that is Dependent on Ketohexokinase. (2019)
  • Author(s): Takahiro Hayasaki, Takuji Ishimoto, Tomohito Doke, Akiyoshi Hirayama, Tomoyoshi Soga, Kazuhiro Furuhashi, Noritoshi Kato, Tomoki Kosugi, Naotake Tsuboi, Miguel A Lanaspa, Richard J Johnson, Shoichi Maruyama, Kenji Kadomatsu
  • Journal Title: J Nutr Biochem Volume: 71 Pages: 54-62
  • DOI: 10.1016/j.jnutbio.2019.05.017
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Lacking Ketohexokinase-A Exacerbates Renal Injury in Streptozotocin-induced Diabetic Mice. (2018)
  • Author(s): Tomohito Doke, Takuji Ishimoto, Takahiro Hayasaki, Satsuki Ikeda, Masako Hasebe, Akiyoshi Hirayama, Tomoyoshi Soga, Noritoshi Kato, Tomoki Kosugi, Naotake Tsuboi, Miguel A. Lanaspa, Richard J. Johnson, Kenji Kadomatsu, and Shoichi Maruyama
  • Journal Title: Metabolism Volume: 85 Pages: 161-170
  • DOI: 10.1016/j.metabol.2018.03.020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] The role of fructose metabolism in vascular endothelial function in diabetes (2020)
  • Author(s): Takuji Ishimoto, Tomohito Doke, Takahiro Hayasaki, Noritoshi Kato, and Shoichi Maruyama
  • Organizer: 18th Asian Pacific Congress of Nephrology
  • Int'l Joint Research
• [Presentation] THE ROLES OF KETOHEXOKINASE DEPENDENT FRUCTOSE METABOLISM IN THE BLOOD PRESSURE REGULATION IN MICE. (2020)
  • Author(s): Takuji Ishimoto, Takahiro Hayasaki, Tomohito Doke, Mayumi Mori-Kawabe, Shoichi Maruyama
  • Organizer: World Congress of Nephrology 2020
  • Int'l Joint Research
• [Presentation] THE ROLES OF KETOHEXOKINASE IN RENAL SODIUM REABSORPTION AND ENDOTHELIAL FUNCTION IN MICE (2020)
  • Author(s): T. Ishimoto, T. Hayasaki, T. Doke, M. Mori-Kawabe, S. Maruyama.
  • Organizer: World Congress of Neurology2020
  • Int'l Joint Research
• [Presentation] LACKING FRUCTOKINASE PREVENTS RENAL LIPID ACCUMULATION IN HIGH-FAT DIET-FED STREPTOZOTOCIN INDUCED DIABETIC MICE (2019)
  • Author(s): T. Doke, T. Ishimoto, T. Hayasaki, T. Tsuboi, R. Johnson, S. Maruyama.
  • Organizer: World Congress of Nephrology
  • Int'l Joint Research
• [Presentation] Renal phospholipid accumulation in high-fat diet fed streptozotocin induced diabetic mice depends on ketohexokinase (2018)
  • Author(s): Tomohito Doke, Takuji Ishimoto, Takahiro Hayasaki, Richard J Johnson, and Shoichi Maruyama
  • Organizer: American Society of Nephrology, Kidney week
  • Int'l Joint Research