Developing the kinetic approach to treat the metabolic disorder from the bilateral side of proximal tubules

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16056
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Keio University
• Principal Investigator: Noguchi Saki 慶應義塾大学, 薬学部(芝共立), 助教 (10803661)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: トランスポーター / 近位尿細管 / メチルマロン酸 / 有機アニオン

Outline of Final Research Achievements

Of organic anion transporters (OAT) evaluated in this study (OAT1, OAT3, and OAT4), OAT1-mediated transport of methylmalonic acid was indicated. Furthermore, the uptake of methylmalonic acid by rat kidney slice was inhibited by probenecid, an OAT inhibitor. Since OAT1 is responsible for the renal secretion of various drugs by basolateral uptake at the blood facing membrane, OAT1-mediated uptake of methylmalonic acid from the plasma may be involved in the renal toxicity and urinary secretion of methylmalonic acid in methylmalonic acidemia. With respect to methylmalonic acid transport on the luminal side of renal epithelia, sodium ion-dependent uptake of methylmalonic acid by rat renal brush border membrane vesicles was detected. However, overexpression of sodium-dependent dicarboxylate transporter 1 (NaDC1) and sodium-coupled monocarboxylate transporter 2 (SMCT2) had negligible effect on the cellular uptake of methylmalonic acid.

Free Research Field

生物薬剤学

Academic Significance and Societal Importance of the Research Achievements

トランスポーターによるメチルマロン酸の輸送について検討し、OAT1がメチルマロン酸を基質認識することを見出した。メチルマロン酸血症患者における腎障害は近位尿細管で観察されることから、OAT1がメチルマロン酸による腎障害発症に関与している可能性がある。トランスポーターによる有機酸の基質認識は、有機酸代謝異常症における新規薬物治療法を開発したり疾患時の薬物腎クリアランスの変動について予測したりする上で重要な知見となり得る。