Association of amino acids in autosomal dominant polycystic kidney disease progression

• Project/Area Number: 20K08603
• 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: Hokkaido University
• Principal Investigator: Nishio Saori 北海道大学, 大学病院, 講師 (90463736)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 常染色体顕性多発性嚢胞腎 / アミノ酸 / LAT1 / トルバプタン / LAT1阻害薬 / 常染色体優性多発性嚢胞腎 / 多発性嚢胞腎 / アミノ酸トランスポーター

Outline of Research at the Start

常染色体優性遺伝性多発嚢胞腎（Autosomal Dominant Polycystic Kidney Disease： ADPKD）は、60歳までに約半数が腎不全に至る最も多い遺伝性腎疾患である。ADPKDの根本的治療薬は、現在はバソプレシンV2受容体拮抗薬であるトルバプタンしかなく、多飲・多尿などの副作用もあることから、新規治療薬の開発が必要である。我々はこれまでに、ADPKDの悪化にアミノ酸が関わっていることを明らかにした。本研究ではADPKD進展にアミノ酸の輸送に関与するLAT1がどの様に関わっているかを明らかにし、新しい治療に結びつける予定である。

Outline of Final Research Achievements

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder characterized by progressive cyst formation in the kidneys, resulting in bilateral renal enlargement, structural damage and kidney failure. The purpose of this study was to elucidate the involvement of amino acids in the progression of ADPKD and to develop new therapeutic agents. L-type amino acid transporter 1 (LAT1) is one of the transmembrane proteins to deliver essential amino acids. Analysis of Pkd1 and LAT1 double knockout mice accelerated cyst formation via amino acids sensing mechanism. However, appropriate suppression of amino acids by drugs suppresses cyst progression.
We found LAT1 inhibitor ameliorates cystogenesis. Furthermore, we found that the combination of LAT1 inhibitor and tolvaptan inhibits the progression of cysts. These treatments may become new treatments in the future.

Academic Significance and Societal Importance of the Research Achievements

ADPKDは遺伝性腎疾患でも最も多く60歳までに約半数が末期腎不全に至る疾患である。治療薬は現在トルバプタンのみであるが、多飲・多尿などの副作用があり、新たな治療薬の開発が急務である。本研究でアミノ酸吸収を阻害することが治療に結びつき、かつトルバプタン併用で治療効果が増強することを明らかにした。この結果から新規治療薬の開発に繋がる可能性がある。

Research Products

• [Journal Article] Cystic Kidney Diseases That Require a Differential Diagnosis from Autosomal Dominant Polycystic Kidney Disease (ADPKD). (2022)
  • Author(s): Sekine A, Hidaka S, Moriyama T, Shikida Y, Shimazu K, Ishikawa E, Uchiyama K, Kataoka H, Kawano H, Kurashige M, Sato M, Suwabe T, Nakatani S, Otsuka T, Kai H, Katayama K...
  • Journal Title: J Clin Med. Volume: 11 Issue: 21 Pages: 6528-6528
  • DOI: 10.3390/jcm11216528
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Soluble Interleukin-2 Receptor Predicts Treatment Outcome in Patients With Autoimmune Tubulointerstitial Nephritis. A Preliminary Study. (2022)
  • Author(s): Shiratori-Aso S, Nakazawa D, Nishio S, Ueda Y, Eguchi M, Yokoyama A, Yoshikawa J, Kudo T, Watanabe-Kusunoki K, Takeda-Otera S, Yamamoto J, Matsuoka N, Kaneshima N, Hattanda F, Iwasaki S, Tsuji T, Fukasawa Y, Atsumi T
  • Journal Title: Front Med (Lausanne) . Volume: Feb25 Pages: 827388-827388
  • DOI: 10.3389/fmed.2022.827388
  • Peer Reviewed
• [Journal Article] A digest from evidence-based Clinical Practice Guideline for Polycystic Kidney Disease 2020 (2021)
  • Author(s): Saori Nishio , Ken Tsuchiya , Shinya Nakatani , Satoru Muto , Toshio Mochizuki , Haruna Kawano, et. al.
  • Journal Title: Clin Exp Nephrol . Volume: 25(12) Issue: 12 Pages: 1292-1302
  • DOI: 10.1007/s10157-021-02097-6
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of administration of single- and triple-course steroid pulse therapy combined with tonsillectomy for immunoglobulin A nephropathy (2021)
  • Author(s): Watanabe-Kusunoki K, Nakazawa D, Yamamoto J, Matsuoka N, Kaneshima N, Nakagaki T, Yamamoto R, Maoka T, Iwasaki S, Tsuji T, Fukasawa Y, Nishimoto N, Nishio S, Atsumi T
  • Journal Title: Medicine (Baltimore) Volume: Apr2100(50) Issue: 4 Pages: 1135-1144
  • DOI: 10.1007/s40620-022-01279-z
  • Peer Reviewed
• [Journal Article] Factors predicting decline in renal function and kidney volume growth in autosomal dominant polycystic kidney disease: a prospective cohort study (Japanese Polycystic Kidney Disease registry: J-PKD) (2021)
  • Author(s): Uchiyama K, Mochizuki T, Shimada Y, Nishio S, Kataoka H, Mitobe M, Tsuchiya K, Hanaoka K, Ubara Y, Suwabe T, Sekine A, Nutahara K, Tsuruya K, Ishimura E, Nakatani S, Sofue T, Tanaka S, Narita I, Maruyama S, Horie S, Muto S.
  • Journal Title: Clin Exp Nephrol Volume: 25 Issue: 9 Pages: 970-980
  • DOI: 10.1007/s10157-021-02068-x
  • Peer Reviewed / Open Access
• [Journal Article] Better remission rates in elderly Japanese patients with primary membranous nephropathy in nationwide real-world practice: The Japan Nephrotic Syndrome Cohort Study (JNSCS) (2020)
  • Author(s): Yokoyama Hitoshi、Yamamoto Ryohei、Imai Enyu、Maruyama Shoichi、Sugiyama Hitoshi、et al.
  • Journal Title: Clinical and Experimental Nephrology Volume: 24 Issue: 10 Pages: 893-909
  • DOI: 10.1007/s10157-020-01913-9
  • Peer Reviewed / Open Access
• [Journal Article] Recombinant thrombomodulin ameliorates autoimmune vasculitis via immune response regulation and tissue injury protection (2020)
  • Author(s): Watanabe-Kusunoki Kanako、Nakazawa Daigo、Kusunoki Yoshihiro、Kudo Takashi、Hattanda Fumihiko、Nishio Saori、Masuda Sakiko、Tomaru Utano、Kondo Takeshi、Atsumi Tatsuya、Ishizu Akihiro
  • Journal Title: Journal of Autoimmunity Volume: 108 Pages: 102390-102390
  • DOI: 10.1016/j.jaut.2019.102390
  • Peer Reviewed / Open Access
• [Journal Article] Increased urinary exosomal SYT17 levels in chronic active antibody-mediated rejection after kidney transplantation via the IL-6 amplifier (2020)
  • Author(s): Takada, Y. Kamimura, D. Jiang, J, Higuchi, H. Iwami, D. Hotta, K. Tanaka, Y. Ota, M. Higuchi, M. Nishio, S. Atsumi, T. Shinohara, N. Matsuno, Y. Tsuji, T. Tanabe, T. Sasaki, H. Iwahara, N. Murakami, M.
  • Journal Title: Int Immunol Volume: 32 Issue: 10 Pages: 653-662
  • DOI: 10.1093/intimm/dxaa032
  • NAID: 120007160285
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Incidence of remission and relapse of proteinuria, end-stage kidney disease, mortality, and major outcomes in primary nephrotic syndrome: the Japan Nephrotic Syndrome Cohort Study (JNSCS) (2020)
  • Author(s): Yamamoto Ryohei、Imai Enyu、Maruyama Shoichi、Yokoyama Hitoshi、Sugiyama Hitoshi、et al.
  • Journal Title: Clinical and Experimental Nephrology Volume: 24 Issue: 6 Pages: 526-540
  • DOI: 10.1007/s10157-020-01864-1
  • Peer Reviewed / Open Access