| Project/Area Number |
21K16181
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53040:Nephrology-related
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
Matsuura Yoshiaki 東京医科歯科大学, 大学院医歯学総合研究科, 非常勤講師 (90880518)
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| Project Period (FY) |
2021-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2022: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2021: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | 慢性腎臓病 / 線維化 / 脂質 / PGD2 / Alox15 / 腎線維化 / 多価不飽和脂肪酸 |
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| Outline of Research at the Start |
本邦の慢性腎臓病（CKD）患者は増加傾向にあり、病態に直接アプローチする治療法の開発が喫緊の課題である。多価不飽和脂肪酸とその代謝物は慢性炎症を主体とする病態形成に関わるが、近年脂質メディエーターを網羅的に解析することで単独で機能を持ち病態に関わる脂肪酸の特定が可能になった。本研究ではCKD腎臓における脂質メディエーターの全体像を明らかにし、病態形成に関わる脂肪酸を明らかにしたい。腎組織の網羅的リピドミクスはこれまで報告がなく、CKDの新規治療開発に繋がる新たな発見が期待される。
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| Outline of Final Research Achievements |
Lipid-metabolizing enzymes and their metabolites affect inflammation and fibrosis, but their roles in chronic kidney disease (CKD) have not been completely understood. In 5/6 Nx kidneys, both mRNA and protein levels of Alox15 were higher when compared with those in sham kidneys. Alox15－/－ CKD mice exhibited better renal functions than wild-type mice. Interstitial fibrosis was also inhibited in Alox15－/－ CKD mice. Mediator lipidomics revealed that Alox15－/－ CKD mouse kidneys had significantly higher levels of PGD2 than the control. To investigate the effects of PGD2 on renal fibrosis, we administered PGD2 to TGF-β1-stimulated NRK-52E cells and HK-2 cells, which lead to a dose-dependent suppression of type I collagen and αSMA in both cell lines. Increased PGD2 in Alox15－/－ CKD mouse kidneys could inhibit fibrosis, thereby resulting in CKD improvement. Thus, Alox15 inhibition and PGD2 administration may be novel therapeutic targets for CKD.
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| Academic Significance and Societal Importance of the Research Achievements |
ALOX15の阻害またはPGD2の投与は，CKDの有望な治療標的となり得る．
本研究により，Alox15のmRNA及びタンパクが共にCKD 腎で増加し，Alox15-/- CKDマウスは野生型CKDマウスと比較して腎機能障害と線維化が抑制されることが明らかになった．さらに，Alox15-/- CKDマウスのCKD腎で増加した脂質代謝物であるPGD2は，近位尿細管培養細胞の上皮間葉転換と線維化を抑制した．Alox15の阻害またはPGD2の投与は，CKDおよび線維化の新規治療標的となる可能性がある．
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