2022 Fiscal Year Final Research Report
Arginine metabolism and autophagy, elucidation of mitochondrial protection mechanism in kidney
Project/Area Number |
20K08610
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 53040:Nephrology-related
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Research Institution | Kyushu University |
Principal Investigator |
TORISU KUMIKO 九州大学, 医学研究院, 准教授 (20448434)
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Co-Investigator(Kenkyū-buntansha) |
中野 敏昭 九州大学, 医学研究院, 准教授 (10432931)
土本 晃裕 九州大学, 大学病院, 助教 (50572103)
原 雅俊 福岡歯科大学, 口腔歯学部, 助教 (60626092)
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Keywords | 腎臓線維化 / 慢性腎臓病 / アルギニン代謝 / スペルミジン / オートファジー |
Outline of Final Research Achievements |
Here we report that arginine metabolism was the most altered in unilateral ureteral obstruction (UUO)-induced fibrosis of the kidneys in metabolomic analysis. Spermidine was the most increased metabolite of arginine. In human glomerulonephritis, the amount of spermidine was associated with the amount of fibrosis. In human proximal tubule cells, spermidine induced nuclear factor erythroid 2-related factor 2 (Nrf2), and its induction was partly attenuated by the autophagy inhibitor, hydroxychloroquine and Atg5 knockdown. Subsequently, fibrotic signals, collagen 1 mRNA, and oxidative stress, represented by a decrease in mitochondrial membrane potential were suppressed by spermidine. UUO kidneys of Arg2 knockout mice showed less spermidine and significantly exacerbated fibrosis compared with wild-type mice. Nrf2 activation was reduced in Arg2 knockout UUO kidneys. Spermidine treatment prevented significant fibrosis progression in Arg2 knockout mice.
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Free Research Field |
腎臓内科
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Academic Significance and Societal Importance of the Research Achievements |
アルギニンの代謝物であるスペルミジンは抗加齢因子として以前から注目されていたが、スペルミジンの加齢変化を抑制する作用機序はわかっていない。腎臓線維化はすべての腎臓病の最終形態であるが、その線維化をスペルミジンにより抑制できることを見出したことは、慢性腎臓病の治療薬の可能性を広げる発見である。スペルミジンは生体内にある代謝物であるため、安全に治療応用ができる。生体内でスペルミジンの量を増やすこと、もしくはスペルミジンの摂取をすることで慢性腎臓病の進行を抑制できる可能性がある。
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