Novel therapeutic strategies for drug-induced kidney injury: Development of prevention and testing methods targeting megalin

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K19480
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: Niigata University
• Principal Investigator: Aoki Nobumasa 新潟大学, 医歯学系, 助教 (60646933)
• Project Period (FY): 2016-04-01 – 2019-03-31
• 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

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.

Free Research Field

感染症内科学、呼吸器内科学、腎臓内科学

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。