Elucidation of renoprotective effects of an SGLT2 inhibitor through analysis of renal energy metabolism by an imaging mass spectrometry

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09710
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Keio University
• Principal Investigator: HAGIWARA Aika 慶應義塾大学, 医学部(信濃町), 共同研究員 (00627052)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: SGLT2阻害薬 / アデニル酸代謝 / 腎保護効果

Outline of Final Research Achievements

Metabolome analysis revealed a decrease in ATP level in the kidneys of tofogliflozin-treated mice and an increase in ATP degradation products, including adenosine. Direct injection of adenosine in the renal artery induced activation of HSL in the white and brown adipose tissues. These results indicate that the renal afferent nerves mediate the lipolytic effect of an SGLT2 inhibitor in obese mice. The alterations to the renal energy metabolism can play significant roles in the lipolysis through the renal afferent nerves and body weight reduction by tofogliflozin. An xanthine oxidase inhibitor, febuxostat, which blocks the degradation pathway of adenine nucleotides, promoted ATP recovery and exerted renoprotective effects in the postischemic kidney.
These findings suggest a novel therapeutic approach for the chronic kidney disease through modification of renal metabolism.

Free Research Field

腎臓内分泌代謝内科学

Academic Significance and Societal Importance of the Research Achievements

今回、申請者らは世界で初めて腎マスイメージングによるエネルギー代謝産物の可視化に成功し、その手法を用いてSGLT2阻害薬の腎保護効果を代謝変容の是正に着想した点に学術的意義があると考える。また、今回検討したアデニル酸代謝、またそれら経路の代謝酵素を標的とした腎保護戦略は、全ての腎不全において最終共通経路である慢性腎虚血に対して有効となる可能性が考えられ、成因が多岐にわたる腎不全において非常に広い患者層での臨床応用が期待され、その社会的意義は大きいと思われる。