Published papers

Growth Hormone Secretagogue receptor(GHSR)欠損マウス、対照マウス、GHSR欠損ECマウス(GHSR欠損マウスで内皮細胞にのみGHSRの発現を回復させたマウス)の各3群のマウスで高脂肪食負荷を行い、内皮GHSRの脂質蓄積作用、エネルギー代謝における役割を検証した。3群のマウスに高脂肪食負荷を行ったところ、白色脂肪組織重量を増加させた。白色脂肪重量の増加と一致してGHSR欠損ECマウスでは糖代謝がGHSR欠損マウスと比較して悪化していた。培養内皮細胞では、グレリン刺激によりCd36、Ap2、Gpihbp1などの脂質取り込み遺伝子の発現の増加と遊離脂肪酸(FFA)の取り込みの増加が認められた。これらの効果はGHSR欠損マウス由来の内皮細胞では観察されなかった。siRNAによりPPARγを欠損させるとグレリンの脂質吸収作用が認められず、グレリン/GHSRシグナルが内皮PPARγを介してFFAの取り込みを促進させることを明らかにした。以上の結果から内皮GHSRがグレリンに反応して白色脂肪細胞への脂質の取り込みを増加させ白色脂肪重量および脂質代謝を調節することを明らかにした。

Although oxidative stress plays central roles in postischemic renal injury, region-specific alterations in energy and redox metabolism caused by short-duration ischemia remain unknown. Imaging mass spectrometry enabled us to reveal spatial heterogeneity of energy and redox metabolites in the postischemic murine kidney. After 10-minute ischemia and 24-hour reperfusion (10mIR), in the cortex and outer stripes of the outer medulla, ATP substantially decreased, but not in the inner stripes of the outer medulla and inner medulla. 10mIR caused renal injury with elevation of fractional excretion of sodium, although histological damage by oxidative stress was limited. Ischemia-induced NADH elevation in the cortex indicated prolonged production of reactive oxygen species by xanthine oxidase (XOD). However, consumption of reduced glutathione after reperfusion suggested the amelioration of oxidative stress. An XOD inhibitor, febuxostat, which blocks the degradation pathway of adenine nucleotides, promoted ATP recovery and exerted renoprotective effects in the postischemic kidney. Because effects of febuxostat were canceled by silencing of the hypoxanthine phosphoribosyl transferase 1 gene in cultured tubular cells, mechanisms for the renoprotective effects appear to involve the purine salvage pathway, which uses hypoxanthine to resynthesize adenine nucleotides, including ATP. These findings suggest a novel therapeutic approach for acute ischemia/reperfusion renal injury with febuxostat through salvaging high-energy adenine nucleotides.