Elucidation of the role of tryptophan metabolism in diabetic nephropathy: Towards a development of novel treatment of diabetic nephropathy targeting tryptophan metabolism

• Project/Area Number: 19K08715
• 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: Fujita Health University
• Principal Investigator: Yuzawa Yukio 藤田医科大学, 医学部, 教授 (00191479)
• Co-Investigator(Kenkyū-buntansha): 長尾 静子 藤田医科大学, 疾患モデル教育研究サポートセンター, 教授 (20183527) ; 倉橋 浩樹 藤田医科大学, 総合医科学研究所, 教授 (30243215) ; 坪井 直毅 藤田医科大学, 医学部, 教授 (50566958) ; 鍋島 俊隆 藤田医科大学, 保健学研究科, 客員教授 (70076751) ; 齋藤 邦明 藤田医科大学, 保健学研究科, 教授 (80262765) ; 高橋 和男 藤田医科大学, 医学部, 教授 (90631391)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 糖尿病性腎症 / 糖尿病性腎臓病 / トリプトファン代謝物 / メタボローム解析 / 糖尿性腎臓病 / 尿細管障害 / NMDA受容体 / トリプトファン代謝 / NMDA受容体拮抗薬 / トリプトファン / キヌレニン / バイオマーカー / メタボロミクス / 疾患モデル

Outline of Research at the Start

糖尿病性腎症の病理学的変化は糖尿病初期から認め，その進展抑制には早期診断及び長期にわたる治療戦略が必要である。我々は，糖尿病性腎症の臓器連関の解明を目的とした網羅的メタボローム解析から多臓器連関を持つトリプトファン（TRP）代謝経路が糖尿病性腎症の発症進展に関わることを見出した。そこで，本研究では2型糖尿病におけるTRP代謝変容の腎症における役割の解明とTRP代謝物のバイオマーカー応用を目指す。

Outline of Final Research Achievements

We have recently demonstrated that the tryptophan (TRP) metabolites were involved in the development of diabetic nephropathy based on metabolome analysis. Thus, we aimed to elucidate the role of TRP metabolism in diabetic nephpathy, to apply TRP metabolites as biomakers, and to develop novel target of treatment of diabtic nephropathy trough animal model. We found that NMDA receptor-mediated tubular damage caused by the metabolite quinolinic acid is associated with worsening of diabetic nephropathy.

Academic Significance and Societal Importance of the Research Achievements

本研究により初めてトリプトファン代謝物が腎症悪化に関連することが示唆され，新規治療標的となることが明らかとなった。キノリン酸はNMDA受容体を介した神経細胞毒性が知られているが，尿細管細胞にはキノリン酸単独の障害性は低いことがわかった。またNMDA受容体拮抗薬による進行腎症に対する抑制効果は認めなかった。今後キノリン酸による尿細管障害への影響の解明や上皮細胞への影響を検討することにより，糖尿病性腎症の新規治療の開発が期待できる。

Research Products

• [Journal Article] Hepatocellular carcinoma induces body mass loss in parallel with osmolyte and water retention in rats (2022)
  • Author(s): Kidoguchi Satoshi、Kitada Kento、Nakajima Kazuki、Nakano Daisuke、Ohsaki Hiroyuki、Kittikulsuth Wararat、Kobara Hideki、Masaki Tsutomu、Yokoo Takashi、Takahashi Kazuo、Titze Jens、Nishiyama Akira
  • Journal Title: Life Sciences Volume: 289 Pages: 120192-120192
  • DOI: 10.1016/j.lfs.2021.120192
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Serum hemoglobin concentration and risk of renal function decline in early stages of diabetic kidney disease: a nationwide, biopsy-based cohort study (2021)
  • Author(s): Yamanouchi M,Furuichi K,Shimizu M,Toyama T,Yamamura Y,Oshima M,Kitajima S,Hara A,Iwata Y,Sakai N,Oba Y,Matsuoka S,Ikuma De,Mizuno H,Suwabe T,Hoshino J Sawa N,Yuzawa Y,Kitamura H,Suzuki Y,Sato H,Uesugi N,Ueda Y,Nishi S,Yokoyama H,Nishino T,Samejima K Kohagura K,Shibagaki Y,Makino H,Matsuo S,Ubara Y,Wada
  • Journal Title: Nephrology Dialysis Transplantation Volume: 37 Issue: 3 Pages: 489-497
  • DOI: 10.1093/ndt/gfab185
  • Peer Reviewed / Open Access
• [Journal Article] Aberrantly Glycosylated IgA1 in IgA Nephropathy: What We Know and What We Don’t Know (2021)
  • Author(s): Ohyama Yukako、Renfrow Matthew B.、Novak Jan、Takahashi Kazuo
  • Journal Title: Journal of Clinical Medicine Volume: 10 Issue: 16 Pages: 3467-3467
  • DOI: 10.3390/jcm10163467
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of aortic valve stenosis in myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis with renal involvement (2021)
  • Author(s): Hasegawa Midori、Iwasaki Jin、Sugiyama Satoshi、Ishihara Takuma、Yamamoto Yoshihiro、Asada Hiroaki、Koide Shigehisa、Hayashi Hiroki、Takahashi Kazuo、Inaguma Daijo、Yuzawa Yukio、Tsuboi Naotake
  • Journal Title: PLOS ONE Volume: 16 Issue: 1 Pages: e0245869-e0245869
  • DOI: 10.1371/journal.pone.0245869
• [Journal Article] Long-term changes in renal function after treatment initiation and the importance of early diagnosis in maintaining renal function among IgG4-related tubulointerstitial nephritis patients in Japan (2020)
  • Author(s): Arai Haruna、Ogata Soshiro、Ozeki Takaya、Takahashi Kazuo、Tsuboi Naotake、Maruyama Shoichi、Inaguma Daijo、Hasegawa Midori、Yuzawa Yukio、Hayashi Hiroki
  • Journal Title: Arthritis Research & Therapy Volume: 22 Issue: 1
  • DOI: 10.1186/s13075-020-02320-x
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of the 2018 and 2003 International Society of Nephrology/Renal Pathology Society classification in terms of renal prognosis in patients of lupus nephritis: a retrospective cohort study (2020)
  • Author(s): Umeda Ryosuke、Ogata Soshiro、Hara Shigeo、Takahashi Kazuo、Inaguma Daijo、Hasegawa Midori、Yasuoka Hidetaka、Yuzawa Yukio、Hayashi Hiroki、Tsuboi Naotake
  • Journal Title: Arthritis Research & Therapy Volume: 22 Issue: 1
  • DOI: 10.1186/s13075-020-02358-x
  • Peer Reviewed / Open Access
• [Journal Article] Extreme hyperuricemia is a risk factor for infection-related deaths in incident dialysis patients: a multicenter prospective cohort study (2020)
  • Author(s): Yoshida Hiroyuki、Inaguma Daijo、Koshi-Ito Eri、Ogata Soshiro、Kitagawa Akimitsu、Takahashi Kazuo、Koide Shigehisa、Hayashi Hiroki、Hasegawa Midori、Yuzawa Yukio、Tsuboi Naotake
  • Journal Title: Renal Failure Volume: 42 Issue: 1 Pages: 646-655
  • DOI: 10.1080/0886022x.2020.1788582
• [Journal Article] Analysis of O-glycoforms of the IgA1 hinge region by sequential deglycosylation. (2020)
  • Author(s): Ohyama Y, Yamaguchi H, Nakajima K, Mizuno T, Fukamachi Y, Yokoi Y, Tsuboi N, Inaguma D, Hasegawa M, Renfrow MB, Novak J, Yuzawa Y, Takahashi K.
  • Journal Title: Sci Rep. Volume: 10(1) Issue: 1 Pages: 671-671
  • DOI: 10.1038/s41598-020-57510-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD140b and CD73 are markers for human induced pluripotent stem cell‐derived erythropoietin‐producing cells (2019)
  • Author(s): Nishimoto S, Mizuno T, Naagamatsu T. et al.
  • Journal Title: FEBS Open Bio Volume: 10 Issue: 3 Pages: 427-433
  • DOI: 10.1002/2211-5463.12800
  • NAID: 120006879490
  • Peer Reviewed / Open Access
• [Presentation] Alteration of Tryptophan-Kynurenine Metabolites in the Serum and Kidney in Diabetic Nephropathy (2019)
  • Author(s): Shoko Matsushita,Kazuo Takahashi,Ryosuke Umeda,Naotake Tsuboi,Kazuki Nakajima,1 Aya Yoshimura,1 Kanako Kumamoto,1 Masanori Kugita,1 Hidetsugu Fujigaki,1 Akihiro Mouri,1 Yasuko Yamamoto,1 Toshitaka Nabeshima,Mitsutoshi Setou,Shizuko Nagao,Kuniaki Saito,Yukio Yuzawa
  • Organizer: Kidney Week 2019
  • Int'l Joint Research
• [Presentation] 糖尿病性腎症における代謝変容の役割の解明 (2019)
  • Author(s): 高橋和男、坪井直毅、長尾静子、齋藤邦明、湯澤由紀夫
  • Organizer: 第49回日本腎臓学会西部学術大会
  • Invited
• [Presentation] 2型糖尿病性腎症モデルラットにおける腎組織中キノリン酸の分布解析 (2019)
  • Author(s): 松下祥子、高橋和男、吉村文、熊本海生航、伊藤辰将、坪井直毅、毛利彰宏3、山本 康子4、藤垣 英嗣4、中嶋和紀、釘田雅則、國澤和生、鍋島俊隆、齋藤邦明、瀬藤光利、長尾静子、湯澤由紀夫
  • Organizer: 第62回日本腎臓学会学術総会