Development of new treatment strategy for chronic kidney disease using medical big data

• Project/Area Number: 18K14983
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Tokushima Bunri University (2020); The University of Tokushima (2018-2019)
• Principal Investigator: HORINOUCHI YUYA 徳島文理大学, 薬学部, 講師 (30716593)
• 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: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 医療ビッグデータ / FAERS / 慢性腎臓病 / 急性腎障害 / 慢性腎障害

Outline of Final Research Achievements

We investigated the protective effects of an FXa inhibitor against renal tubulointerstitial injury using unilateral ureteral obstruction (UUO) mice (a renal tubulointerstitial fibrosis model) and the Food and Drug Administration Adverse Events Reporting System (FAERS) database. The renal expression levels of FX and the FXa receptors protease-activated receptor(PAR)-1 and PAR-2 were higher in UUO mice than in sham-operated mice. UUO-induced tubulointerstitial fibrosis, extracellular matrix expression, macrophage infiltration and inflammatory molecule upregulation were suppressed in UUO mice treated with the FXa inhibitor edoxaban. In an analysis of the FAERS database, there were significantly fewer reports of tubulointerstitial nephritis for patients treated with FXa inhibitors than for patients not treated with inhibitors. These results suggest that FXa inhibitors exert protective effects against chronic kidney disease by inhibiting tubulointerstitial fibrosis.

Academic Significance and Societal Importance of the Research Achievements

超高齢社会日本において、透析予備軍である慢性腎臓病患者数は1,300万人以上と言われており、慢性腎臓病を惹起・進展させないことは非常に重要なため、慢性腎臓病の病態解明と新規治療法の開発は喫緊の課題である。
本研究では、基礎研究と医療ビッグデータ解析により既存薬であるFXa阻害剤が慢性腎臓病の新規治療候補薬になる可能性を見出した。既存薬であるため、臨床的な安全性が確立されており、新たな副作用のリスクが低いと考えられ、今後の臨床応用が期待される。

Research Products

• [Journal Article] Investigation of drugs affecting hypertension in bevacizumab‐treated patients and examination of the impact on the therapeutic effect (2020)
  • Author(s): Yagi Kenta、Mitstui Marin、Zamami Yoshito、Niimura Takahiro、Izawa‐Ishizawa Yuki、Goda Mitsuhiro、Chuma Masayuki、Fukunaga Kimiko、Shibata Takahiro、Ishida Shunsuke、Sakurada Takumi、Okada Naoto、Hamano Hirofumi、Horinouchi Yuya、Ikeda Yasumasa、Yanagawa Hiroaki、Ishizawa Keisuke
  • Journal Title: Cancer Medicine Volume: 10 Issue: 1 Pages: 164-172
  • DOI: 10.1002/cam4.3587
  • NAID: 120007147667
  • Peer Reviewed / Open Access
• [Journal Article] Deletion of H-ferritin in macrophages alleviates obesity and diabetes induced by high-fat diet in mice (2020)
  • Author(s): Ikeda Yasumasa、Watanabe Hiroaki、Shiuchi Tetsuya、Hamano Hirofumi、Horinouchi Yuya、Imanishi Masaki、Goda Mitsuhiro、Zamami Yoshito、Takechi Kenshi、Izawa-Ishizawa Yuki、Miyamoto Licht、Ishizawa Keisuke、Aihara Ken-ichi、Tsuchiya Koichiro、Tamaki Toshiaki
  • Journal Title: Diabetologia Volume: 63 Issue: 8 Pages: 1588-1602
  • DOI: 10.1007/s00125-020-05153-0
  • NAID: 120007039998
  • Peer Reviewed
• [Journal Article] Fibroblast-specific ERK5 deficiency changes tumor vasculature and exacerbates tumor progression in a mouse model. (2020)
  • Author(s): Masaki Imanishi, Yusuke Yamakawa, Keijo Fukushima, Raiki Ikuto, Akiko Maegawa, Yuki Izawa-Ishizawa, Yuya Horinouchi, Masateru Kondo, Masatoshi Kishuku, Mitsuhiro Goda, Yoshito Zamami, Kenshi Takechi, Masayuki Chuma, Yasumasa Ikeda, Koichiro Tsuchiya, Hiromichi Fujino, Koichi Tsuneyama, Keisuke Ishizawa
  • Journal Title: Naunyn-Schmiedeberg's Archives of Pharmacology Volume: - Issue: 7 Pages: 1239-1250
  • DOI: 10.1007/s00210-020-01859-5
  • Peer Reviewed / Open Access
• [Journal Article] Rho-associated protein kinase and cyclophilin A are involved in inorganic phosphate-induced calcification signaling in vascular smooth muscle cells (2020)
  • Author(s): Tatsuya Tsuda, Masaki Imanishi, Mizuho Oogoshi, Yoshitaka Kihira, Yuya Horinouchi, Yoshito Zamami, Keisuke Ishizawa, Yasumasa Ikeda, Ichiro Hashimoto, Toshiaki Tamaki, Yuki Izawa-Ishizawa
  • Journal Title: Journal of Pharmacological Sciences Volume: 142 Issue: 3 Pages: 109-115
  • DOI: 10.1016/j.jphs.2019.12.005
  • NAID: 120006980541
  • Peer Reviewed / Open Access
• [Journal Article] Proton pump inhibitors block iron absorption through direct regulation of hepcidin via the aryl hydrocarbon receptor-mediated pathway (2020)
  • Author(s): Hamano Hirofumi、Niimura Takahiro、Horinouchi Yuya、Zamami Yoshito、Takechi Kenshi、Goda Mitsuhiro、Imanishi Masaki、Chuma Masayuki、Izawa-Ishizawa Yuki、Miyamoto Licht、Fukushima Keijo、Fujino Hiromichi、Tsuchiya Koichiro、Ishizawa Keisuke、Tamaki Toshiaki、Ikeda Yasumasa
  • Journal Title: Toxicology Letters Volume: 318 Pages: 86-91
  • DOI: 10.1016/j.toxlet.2019.10.016
  • NAID: 120006894295
  • Peer Reviewed / Open Access
• [Journal Article] Body iron accumulation in obesity, diabetes and its complications, and the possibility of therapeutic application by iron regulation (2019)
  • Author(s): Horinouchi Yuya、Ikeda Yasumasa、Tamaki Toshiaki
  • Journal Title: Folia Pharmacologica Japonica Volume: 154 Issue: 6 Pages: 316-321
  • DOI: 10.1254/fpj.154.316
  • NAID: 130007754372
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed
• [Journal Article] Iron accumulation causes impaired myogenesis correlated with MAPK signaling pathway inhibition by oxidative stress (2019)
  • Author(s): Ikeda Yasumasa、Satoh Akiho、Horinouchi Yuya、Hamano Hirofumi、Watanabe Hiroaki、Imao Mizuki、Imanishi Masaki、Zamami Yoshito、Takechi Kenshi、Izawa‐Ishizawa Yuki、Miyamoto Licht、Hirayama Tasuku、Nagasawa Hideko、Ishizawa Keisuke、Aihara Ken‐Ichi、Tsuchiya Koichiro、Tamaki Toshiaki
  • Journal Title: The FASEB Journal Volume: 33 Issue: 8 Pages: 9551-9564
  • DOI: 10.1096/fj.201802724rr
  • NAID: 120006847086
  • Peer Reviewed / Open Access
• [Journal Article] Development of a novel aortic dissection mouse model and evaluation of drug efficacy using in-vivo assays and database analyses (2019)
  • Author(s): Izawa-Ishizawa Yuki、Imanishi Masaki、Zamami Yoshito、Toya Hiroki、Nagao Tomoko、Morishita Marin、Tsuneyama Koichi、Horinouchi Yuya、Kihira Yoshitaka、Takechi Kenshi、Ikeda Yasumasa、Tsuchiya Koichiro、Yoshizumi Masanori、Tamaki Toshiaki、Ishizawa Keisuke
  • Journal Title: Journal of Hypertension Volume: 37 Issue: 1 Pages: 73-83
  • DOI: 10.1097/hjh.0000000000001898
  • NAID: 120006627861
  • Peer Reviewed / Open Access
• [Journal Article] Xanthine oxidase inhibition by febuxostat in macrophages suppresses angiotensin II-induced aortic fibrosis (2018)
  • Author(s): Kondo Masateru、Imanishi Masaki、Fukushima Keijo、Ikuto Raiki、Murai Yoichi、Horinouchi Yuya、Izawa-Ishizawa Yuki、Goda Mitsuhiro、Zamami Yoshito、Takechi Kenshi、Chuma Masayuki、Ikeda Yasumasa、Fujino Hiromichi、Tsuchiya Koichiro、Ishizawa Keisuke
  • Journal Title: American Journal of Hypertension Volume: 32 Issue: 3 Pages: 249-256
  • DOI: 10.1093/ajh/hpy157
  • Peer Reviewed / Open Access
• [Journal Article] Nitrosonifedipine, a photodegradation product of nifedipine, suppresses pharmacologically induced aortic aneurysm formation (2018)
  • Author(s): Imanishi Masaki、Izawa-Ishizawa Yuki、Sakurada Takumi、Kohara Yusuke、Horinouchi Yuya、Sairyo Eriko、Zamami Yoshito、Takechi Kenshi、Chuma Masayuki、Fukushima Keijo、Ikeda Yasumasa、Fujino Hiromichi、Yoshizumi Masanori、Tsuchiya Koichiro、Tamaki Toshiaki、Ishizawa Keisuke
  • Journal Title: Pharmacology Volume: 102 Issue: 5-6 Pages: 287-299
  • DOI: 10.1159/000492577
  • Peer Reviewed / Open Access
• [Journal Article] Irinotecan-induced neutropenia is reduced by oral alkalization drugs: analysis using retrospective chart reviews and the spontaneous reporting database (2018)
  • Author(s): Hamano Hirofumi、Mitsui Marin、Zamami Yoshito、Takechi Kenshi、Nimura Takahiro、Okada Naoto、Fukushima Keijo、Imanishi Masaki、Chuma Masayuki、Horinouchi Yuya、Izawa-Ishizawa Yuki、Kirino Yasushi、Nakamura Toshimi、Teraoka Kazuhiko、Ikeda Yasumasa、Fujino Hiromichi、Yanagawa Hiroaki、Tamaki Toshiaki、Ishizawa Keisuke
  • Journal Title: Supportive Care in Cancer Volume: 27 Issue: 3 Pages: 849-856
  • DOI: 10.1007/s00520-018-4367-y
  • Peer Reviewed / Open Access
• [Journal Article] Renoprotective effects of a factor Xa inhibitor: fusion of basic research and a database analysis (2018)
  • Author(s): Horinouchi Yuya、Ikeda Yasumasa、Fukushima Keijo、Imanishi Masaki、Hamano Hirofumi、Izawa-Ishizawa Yuki、Zamami Yoshito、Takechi Kenshi、Miyamoto Licht、Fujino Hiromichi、Ishizawa Keisuke、Tsuchiya Koichiro、Tamaki Toshiaki
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 10858-10858
  • DOI: 10.1038/s41598-018-29008-2
  • NAID: 120006535061
  • Peer Reviewed / Open Access
• [Journal Article] Mechanisms of the pH- and Oxygen-Dependent Oxidation Activities of Artesunate (2018)
  • Author(s): Tsuda K, Miyamoto L, Hamano S, Morimoto Y, Kangawa Y, Fukue C, Kagawa Y, Horinouchi Y, Xu W, Ikeda Y, Tamaki T, Tsuchiya K
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 41 Issue: 4 Pages: 555-563
  • DOI: 10.1248/bpb.b17-00855
  • NAID: 130006602520
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access
• [Presentation] 基礎研究と医療ビッグデータ解析を融合させたドラッグ・リポジショニングへの試み (2019)
  • Author(s): 堀ノ内裕也、池田康将、福島圭穣、今西正樹、濱野裕章、石澤有紀、座間味義人、武智研志、藤野裕道、石澤啓介、土屋浩一郎、玉置俊晃
  • Organizer: 第40回日本臨床薬理学会学術総会
• [Presentation] 慢性腎不全関連サルコペニアにおける鉄代謝異常 (2019)
  • Author(s): 堀ノ内裕也、池田康将、濱野裕章、今西正樹、福島圭穣、石澤有紀、合田光寛、座間味義人、武智研志、宮本理人、藤野裕道、石澤啓介、土屋浩一郎、玉置俊晃
  • Organizer: 第6回日本サルコペニア・フレイル学会大会
• [Presentation] 慢性腎不全関連骨格筋萎縮における鉄代謝異常 (2019)
  • Author(s): 堀ノ内 裕也、池田 康将、濱野 裕章、今西 正樹、福島 圭穣、合田 光寛、武智 研志、宮本 理人、石澤 有紀、座間味 義人、藤野 裕道、石澤 啓介、土屋 浩一郎、玉置 俊晃
  • Organizer: 第92回日本薬理学会年会
• [Presentation] 疾患における鉄の意義と治療応用 (2019)
  • Author(s): 堀ノ内 裕也、池田 康将、玉置 俊晃
  • Organizer: 第92回日本薬理学会年会
• [Presentation] 肥満・糖尿病における鉄制御の意義 (2019)
  • Author(s): 堀ノ内 裕也、池田 康将、玉置 俊晃
  • Organizer: 第48回日本心脈管作動物質学会
• [Presentation] マクロファージフェリチン欠損は肥満・糖尿病における脂肪炎症を抑制する (2019)
  • Author(s): 堀ノ内 裕也、池田 康将、渡邉 大晃、濱野 裕章、石澤 有紀、今西 正樹、座間味 義人、武智 研志、宮本 理人、石澤 啓介、土屋 浩一郎、玉置 俊晃
  • Organizer: 第48回日本心脈管作動物質学会
• [Presentation] リアルワールドビッグデータを活用した新規腎保護薬の探索 (2018)
  • Author(s): 堀ノ内 裕也、池田 康将、福島 圭穣、濱野 裕章、今西 正樹、石澤 有紀、座間味 義人、武智 研志、藤野 裕道、石澤 啓介、土屋 浩一郎、玉置 俊晃
  • Organizer: 第28回日本医療薬学会年会
• [Presentation] 慢性腎不全関連サルコペニアにおける鉄の関与 (2018)
  • Author(s): 堀ノ内 裕也、池田 康将、濱野 裕章、今西 正樹、福島 圭穣、武智 研志、宮本 理人、石澤 有紀、座間味 義人、藤野 裕道、石澤 啓介、土屋 浩一郎、玉置 俊晃
  • Organizer: 第134回日本薬理学会近畿部会
• [Presentation] リアルワールドデータを活用した新規腎保護薬の探索 (2018)
  • Author(s): 堀ノ内 裕也、池田 康将、福島 圭穣、石澤 有紀、藤野 裕道、玉置 俊晃
  • Organizer: 第48回日本腎臓学会西部学術大会
• [Presentation] Utilizing Real-World Big Data in the Search for New Renoprotective Drugs (2018)
  • Author(s): Yuya Horinouchi、Yasumasa Ikeda、Keijo Fukushima、Masaki Imanishi、Hirofumi Hamano、Yuki Izawa-Ishizawa、Yoshito Zamami、Hiromichi Fujino、Keisuke Ishizawa、Koichiro Tsuchiya、Toshiaki Tamaki
  • Organizer: Joint Hypertension 2018 Scientific Sessions
  • Int'l Joint Research
• [Presentation] マクロファージ鉄の肥満・糖尿病における役割 (2018)
  • Author(s): 堀ノ内 裕也、池田 康将、渡邉 大晃、濱野 裕章、石澤 有紀、今西 正樹、座間味 義人、武智 研志、宮本 理人、石澤 啓介、土屋 浩一郎、玉置 俊晃
  • Organizer: 第42回日本鉄バイオサイエンス学会学術集会
• [Presentation] Renoprotective effects of edoxaban, a factor Xa inhibitor (2018)
  • Author(s): Yuya Horinouchi、Yasumasa Ikeda、Keijo Fukushima、Masaki Imanishi、Yuki Izawa-Ishizawa、Yoshito Zamami、Hiromichi Fujino、Keisuke Ishizawa、Koichiro Tsuchiya、Toshiaki Tamaki
  • Organizer: WCP2018
  • Int'l Joint Research
• [Presentation] 大規模医療情報データベースを活用した新規腎保護薬の探索 (2018)
  • Author(s): 堀ノ内 裕也、池田 康将、福島 圭穣、今西 正樹、濱野 裕章、石澤 有紀、座間味 義人、藤野 裕道、石澤 啓介、土屋 浩一郎、玉置 俊晃
  • Organizer: 医療薬学フォーラム2018 第26回 クリニカルファーマシーシンポジウム
• [Remarks] 徳島大学大学院医歯薬学研究部医科学部門生理系薬理学分野ホームページ
  • URL: http://www.tuyakuri.umin.jp/
• [Remarks] 徳島大学大学院医歯薬学研究部医科学部門生理系薬理学分野
  • URL: http://www.tuyakuri.umin.jp/