Elucidation of the pathophysiology of kidney disease and establishment of drug screening methods based on energy metabolism dynamics

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K16162
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Kyoto University
• Principal Investigator: Yamamoto Shinya 京都大学, 医学研究科, 助教 (90837105)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: ATP / 二光子顕微鏡 / 糸球体 / 腎臓

Outline of Final Research Achievements

We have successfully visualized ATP dynamics of glomeruli in acute kidney injury and found that ATP recovery in the acute phase is inversely correlated with abnormal morphology of podocytes in the chronic phase. We showed that ATP reduction in the acute phase is strongly associated with the glomerular lesions in the chronic phase. We also established a renal slice culture system using ATP visualized mice, which enabled us to observe ATP in all nephron segments. Next, we clarified the respective dependence of ATP production by glycolysis and oxidative phosphorylation in each nephron segment. Furthermore, we administered nephrotoxic drugs to renal slice cultures and found that ATP behavior differed by nephron segment, indicating the cell-specific pharmacological effects from the aspect of energy metabolism.

Free Research Field

腎臓

Academic Significance and Societal Importance of the Research Achievements

ATP可視化マウスと二光子顕微鏡を用いて、急性腎障害時の糸球体のATPイメージングに続き、腎全領域でのATPの観察に世界で初めて成功しました。急性期のATP低下が慢性期の糸球体病変の出現や腎機能低下の進行に強く関わることを示し、この結果は、急性期に細胞内ATPを保つことが、腎予後を改善するために重要であることを示唆しました。さらに腎スライス培養に腎毒性物質を投与し、ネフロンセグメントによってATP挙動が異なることを見出し、エネルギー代謝の側面から、細胞特異的な薬理作用が存在することを示しました。ATP可視化技術が、腎病態解明や腎保護薬や腎障害物質のスクリーニング法の確立に資すると期待できます。