新規細胞エネルギー代謝スクリーニングに基づいた急性腎障害予防薬 / 治療薬の探索と開発

Acute kidney injury（AKI）is a big clinical problem. In addition to high mortality rate, AKI is a potent risk factor of end-stage kidney disease. Ischemia reperfusion injury（IRI）is the leading cause of AKI and we have no specific treatment options to treat AKI. Shifting energy metabolism from mitochondrial respiration to glycolysis may offer a novel therapy against ischemic organ injury. Based on this theory, Meclizine, first-generation antihistamine used for motion sickness and vertigo, was identified in a novel chemical screen. Kidney tubular injury after ischemia reperfusion was significantly decreased in meclizine treated mice compared with the vehicle treated mice（１００mg/kg of meclizine, １７ hours prior to ischemia）. Meclizine treated kidney showed reduced inflammation, oxidative stress and mitochondrial fragmentation after IRI. Meclizine pretreatment reduced mitochondrial oxygen consumption. Reduced cell death and cytochrome c release was found in kidney tubular epithelial cells. Metabolic profiling revealed that Meclizine caused rapid accumulation of cellular phosphoethanolamine（PEtn）. PEtn inhibits mitochondrial respiration and is an intermediate in phosphatidylethanolamine biosynthesis pathway（Kennedy pathway）. In conclusion, Meclizine, or a derivative, is a candidate drug to minimize AKI risk and Kennedy pathway can be a novel therapeutic target for ischiemic kidney injury.