Analysis of metabolic alterations in diabetic kidney disease and development of new treatment strategy by amelioration of metabolic alterations

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17717
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Keio University
• Principal Investigator: Fujii Kentaro 慶應義塾大学, 医学部(信濃町), 助教 (70626390)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 腎虚血 / 糖尿病性腎臓病 / 代謝変容 / アデニル酸代謝 / アミノ酸代謝

Outline of Final Research Achievements

We successfully visualized the metabolic alteration in different parts of the kidney semi-quantitatively by combining MALDI-IMS and metabolome analyses. Febuxostat, a xanthine oxidase inhibitor, increased ATP by promoting re-synthesis of adenine nucleotides via the salvage pathway, and showed reno-protective effect. Metabolomic analysis of streptozotocin-induced diabetic model mice showed increase of BCAA (isoleucine, leucine, and valine) and significant BCAA accumulation, especially in glomeruli. Progressive renal failure and increased total acetylation of histones H3 and H4 in renal tissues were also observed in leucine-treated STZ mice.

Free Research Field

腎臓内科

Academic Significance and Societal Importance of the Research Achievements

腎慢性虚血に伴うアデニル酸喪失の回復のためATP投与やミトコンドリア賦活化などの基礎検討が行われてきたが、実臨床の応用には至っていない。本研究では、尿酸降下薬としてすでに上市されているFebuxostatが、腎アデニル酸を回復させ腎保護効果を示すことが示された。本研究により、腎臓における慢性虚血によるアデニル酸代謝変容の病態メカニズムと, 糖尿病性腎臓病の病態プロセスにおける新たな代謝変容が示され、アデニル酸代謝やアミノ酸代謝の変容への治療介入による、新規腎保護戦略が提案された。