Development of therapeutic strategy for drug-induced renal fibrosis

• Project/Area Number: 18K06783
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Kyoto University
• Principal Investigator: Nakagawa Shunsaku 京都大学, 医学研究科, 助教 (50721916)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 腎線維化 / シスプラチン / アリストロキア酸 / SOX9 / 近位尿細管 / 薬剤性腎障害 / 薬剤製腎障害 / 細胞間相互作用

Outline of Final Research Achievements

Drug-induced nephropathy can lead to not only acute kidney injury but also chronic renal dysfunction. In addition, the decline in renal function narrows down the choice of drugs needed for treatment, so it is important to develop therapeutic strategies that can eliminate renal damage. In this study, we aimed to provide a concept of treatment for drug-induced renal fibrosis. First, gene expression data in human and animal models of kidney diseases was collected from public databases, and genes commonly associated with fibrosis in human and animal models were identified. Then, we confirmed that the genes of interest were up-regulated in several animal models. Therefore, this gene may be a therapeutic target for the suppression of renal fibrosis.

Academic Significance and Societal Importance of the Research Achievements

実臨床において、薬物による腎障害の頻度は少なくない一方で、その治療法は未だ確立されていない。特に、腎障害後に慢性的に腎機能が低下した際には、それを可逆的に回復させることは困難である。本研究では、薬剤による腎線維化に注目し、腎線維化進展の機序解明とそれに基づく治療標的の提示を目指した。その結果、慢性腎臓病患者および腎疾患モデル動物の腎臓において発現が亢進し、線維化促進に関与する遺伝子を見出した。この結果は、将来的に、薬剤性腎障害後の腎機能を回復させる手法の開発につながるものと考える。

Research Products

• [Journal Article] Association of proton pump inhibitors and concomitant drugs with risk of acute kidney injury: a nested case-control study. (2021)
  • Author(s): Ikuta K, Nakagawa S, Momo K, Yonezawa A, Itohara K, Sato Y, Imai S, Nakagawa T, Matsubara K
  • Journal Title: BMJ Open Volume: 11 Issue: 2 Pages: e041543-e041543
  • DOI: 10.1136/bmjopen-2020-041543
  • Peer Reviewed / Open Access
• [Journal Article] Cisplatin, rather than oxaliplatin, increases paracellular permeability of LLC-PK1 cells via activating protein kinase C. (2020)
  • Author(s): Zhang Y, Yonezawa A, Nakagawa S, Imai S, Denda M, Omura T, Nakagawa T, Matsubara K.
  • Journal Title: Drug Metab Pharmacokinet Volume: 35 Issue: 1 Pages: 111-116
  • DOI: 10.1016/j.dmpk.2019.09.001
  • NAID: 120006796498
  • Peer Reviewed
• [Journal Article] Effects of fasting on warfarin sensitivity index in patients undergoing cardiovascular surgery. (2019)
  • Author(s): Katada Y, Nakagawa S, Nishimura A, Sato Y, Taue H, Matsumura K, Yamazaki K, Minakata K, Yano I, Omura T, Imai S, Yonezawa A, Sato Y, Nakagawa T, Minatoya K, Matsubara K.
  • Journal Title: Eur J Clin Pharmacol Volume: 75 Issue: 4 Pages: 561-568
  • DOI: 10.1007/s00228-018-2592-4
  • Peer Reviewed
• [Journal Article] Effect of medication adherence on disease activity among Japanese patients with rheumatoid arthritis. (2018)
  • Author(s): Nakagawa S, Nakaishi M, Hashimoto M, Ito H, Yamamoto W, Nakashima R, Tanaka M, Fujii T, Omura T, Imai S, Nakagawa T, Yonezawa A, Imai H, Mimori T, Matsubara K.
  • Journal Title: PLoS One Volume: 13 Issue: 11 Pages: e0206943-e0206943
  • DOI: 10.1371/journal.pone.0206943
  • NAID: 120006539574
  • Peer Reviewed / Open Access
• [Presentation] 薬剤性腎障害における細胞死と線維化 (2020)
  • Author(s): 中川 俊作
  • Organizer: 日本薬学会第140年会
• [Presentation] 腎尿細管上皮と線維芽細胞の相互作用におけるTMPRSS4の関与 (2018)
  • Author(s): 栗村万由子、中川俊作、佐藤夕紀、大村友博、今井哲司、米澤 淳、中川貴之、松原和夫
  • Organizer: 第68回日本薬学会近畿支部総会・大会