Novel therapeutic strategies for drug-induced kidney injury: Development of prevention and testing methods targeting megalin
| Project/Area Number |
16K19480
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Kidney internal medicine
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| Research Institution | Niigata University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | メガリン / シラスタチン / コリスチン / バンコマイシン / シスプラチン / 薬剤性腎障害 / ゲンタマイシン / トランスレーショナルリサーチ |
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| Outline of Final Research Achievements |
Nephrotoxicity induced by anti-microorganism or anti-cancer drugs is a serious clinical problem. Megalin, an endocytic receptor expressed at the proximal tubules, may mediates the nephrotoxicity of these drugs. The mechanisms underlying the nephrotoxicity are unknown. In this study, using quartz-crystal microbalance analysis, we found that megalin is bound by colistin, vancomycin and cisplatin, and the binding of these drugs to megalin is competed with cilastatin. Using mosaic megalin knockout mice, we revealed that the nephrotoxicity induced by colistin, vancomycin, and cisplatin depends on megalin expression. We showed that colistin-induced nephrotoxicity is suppressed by concomitant cilastatin administration. We also found that cilastatin does not inhibit the anti-bacterial activity of gentamicin, colistin, and vancomycin in vitro. In conclusion, megalin blockade with cilastatin suppresses efficiently the nephrotoxicity induced by gentamicin, colistin, vancomycin, and cisplatin.
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| Academic Significance and Societal Importance of the Research Achievements |
抗菌薬や抗腫瘍薬による腎障害は、使用薬の制限を招き治療効果の減少につながっている。いずれも疾患の予後に影響する重要な要因である。本研究により、腎障害機序の一端が解明されたのみならず、腎障害予防薬の有望な候補薬の同定に至った。臨床応用することで、抗菌薬や抗腫瘍薬の治療効果の増強やより幅広い患者層への投与が可能になると考えられる。また薬剤性腎障害は慢性腎臓病の原因となる可能性もあり、その予防を図ることで腎機能温存の新たな治療戦略の開発が期待される。
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Report
(4 results)
Research Products
(4 results)
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[Journal Article] Megalin Blockade with Cilastatin Suppresses Drug-Induced Nephrotoxicity2017
Author(s)
Hori Y, Aoki N, Kuwahara S, Hosojima M, Kaseda R, Goto S, Iida T, De S, Kabasawa H, Kaneko R, Aoki H, Tanabe Y, Kagamu H, Narita I, Kikuchi T, Saito A.
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Journal Title
J Am Soc Nephrol
Volume: in press
Issue: 6
Pages: 1783-1791
DOI
Related Report
Peer Reviewed / Open Access
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