Lysosomal stress as an emerging target in kidney disease
| Project/Area Number |
18K08208
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53040:Nephrology-related
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| Research Institution | Osaka University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
猪阪 善隆 大阪大学, 医学系研究科, 教授 (00379166)
高橋 篤史 大阪大学, 医学部附属病院, 助教 (10704786)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | リソソーム / オートファジー / 近位尿細管 / 虚血再灌流 / シュウ酸腎症 / TFEB / 結晶腎症 / リソソームストレス / LMP / オートファジーフラックス / 脂質代謝 / 尿細管 / 慢性腎臓病 |
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| Outline of Final Research Achievements |
Autophagy plays an important role in protecting kidney from ischemia-reperfusion injury (IRI); however, in a later phase (48 hours after IRI), enlarged and dysfunctional (as suggested by a decrease in enzymatic activity) lysosomes were observed, which inhibited full activation of autophagy (referred to as “lysosomal stress”). We found that dysregulated lipid metabolism (especially lipid peroxidation) leads to lysosomal stress. PPARα administration alleviated lysosomal stress and IRI. Based on a hypothesis that modulating lysosomal activity alleviates lysosomal stress, we investigated the role of TFEB in various kidney disease models by analyzing TFEB knockout mice (KO mice). We found no difference between wildtype and KO mice subjected to IRI, but in oxalate nephropathy, kidney injury was more exaggerated in KO mice, suggesting that TFEB protects kidney from lysosomal stress during crystal nephropathy. Modulating TFEB activity may be a therapeutic option targeting kidney diseases.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究の結果から、IRIやシュウ酸腎症マウスモデルでは、リソソーム障害（傷害）がオートファジー活性化の阻害などを介して、病態を悪化させている、「リソソームストレス」とも呼ぶべき状態が存在することが判明した。リソソームストレスの特徴の一部は、ヒト腎移植後の腎臓でも認められ、臨床的にも意義を持つものと思われる。IRIの場合、脂質代謝異常がリソソームの機能異常の原因になっており、またノックアウトマウスを用いた実験からは、転写因子TFEBの活性調節がリソソームストレスの解除を介して腎保護につながるものと推測された。今後薬剤による脂質代謝異常の改善やTFEBの活性化が治療の選択肢になり得ると思われる。
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Report
(4 results)
Research Products
(4 results)
