In vivo metabolomic analysis and metabolic alteration-targeted treatment on diabetic nephropathy model .

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K07203
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Genome biology
• Research Institution: Keio University
• Principal Investigator: KUBO Akiko 慶應義塾大学, 医学部(信濃町), 特任助教 (50455573)
• Co-Investigator(Kenkyū-buntansha): 宮下 和季 慶應義塾大学, 医学部(信濃町), 特任准教授 (50378759)
• Research Collaborator: FUJII Kentaro ; SATO Masaaki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: イメージング質量分析

Outline of Final Research Achievements

This study aims to find out how the diabetic nephropathy starts by analyzing local energy metabolism in situ. At first, we develop the method to visualize energy metabolism with healthy mice. The quantitative analyses with capillary-electrophoresis mass spectrometry combined with MALDI imaging mass spectrometry allowed us to know local metabolite contents of a frozen section. Then we compared the local energy metabolism between healthy mouse group and model disease mouse group.
When the energy metabolism status is low, ATP decreases and catabolic products such as hypoxanthine and xanthine increases. Hypoxanthine is converted into uric acid by xanthine oxidase which uses O2 molecule and produces reactive oxygen species (ROS). We tried to prevent ROS production in murine kidney by adding xanthine oxidase inhibitor, and analyzed murine energy metabolism. Successfully xanthine oxidase inhibitor blocked hypoxanthine catabolism and promoted ATP production via salvage pathway.

Free Research Field

分析化学

Academic Significance and Societal Importance of the Research Achievements

糖尿病性腎症の実態をエネルギー代謝の面で評価することは、臨床研究では難しく、腎障害に至る過程の解明が望まれている。この研究では、マウスモデルを用いて、腎臓の領域ごとのエネルギー代謝の可視化解析法を開発し、エネルギー代謝とROSの発生が密接に関係することを明らかにした。エネルギー代謝が分解方向に傾いたときに、痛風の治療に用いられる経口薬を投与することで、腎保護につながることがわかった。今後、心停止からの回復時、腎移植などの際にキサンチンオキシダーゼ阻害剤を投与することで、腎保護効果が期待できる。