| Project/Area Number |
15KT0088
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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 | 特設分野 |
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| Research Field |
Neo-Gerontology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Inagi Reiko 東京大学, 医学部附属病院, 特任准教授 (50232509)
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| Co-Investigator(Kenkyū-buntansha) |
川上 貴久 東京大学, 医学部附属病院, 助教 (10722093)
南学 正臣 東京大学, 医学部附属病院, 教授 (90311620)
田中 哲洋 東京大学, 医学部附属病院, 講師 (90508079)
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| Project Period (FY) |
2015-07-10 – 2018-03-31
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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | ポドサイト / SIRT1 / アセチル化 / cortactin / アクチン細胞骨格 / 糸球体濾過量 / 腎臓老化 / アクチン重合 / アセチル化蛋白 / 糸球体腎炎 / 蛋白尿 / 近位尿細管上皮細胞 / 尿毒素 / D-アミノ酸 / D-セリン / アポトーシス / 細胞周期停止 / SASP / 小胞体ストレス / microRNA / 尿細管上皮細胞 / エピゲノム / microRNA 205 / 酸化ストレス / 低酸素 |
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| Outline of Final Research Achievements |
We investigated the role of SIRT1, a histone deacetylase, in podocytes by using podocyte-specific Sirt1 knockout (SIRT1pod-/-) mice. In the experimental mice with glomerular disease, the disease severity was significantly greater in SIRT1pod-/- mice than in wild-type mice. It was associated with actin cytoskeleton derangement. Actin cytoskeleton derangement in H2O2-treated cultured podocytes became prominent when the cells were pretreated with SIRT1 inhibitors. Importantly, we found that SIRT1 deacetylated actin-binding protein cortactin in the nucleus and that the deacetylated cortactin was localized in the cytoplasm for maintenance of actin cytoskeleton. Cortactin knockdown as well as inhibition of nuclear export of cortactin deranged actin cytoskeleton due to dissociation of cortactin from actin.
We found that SIRT1 protects podocytes and prevents glomerular injury by deacetylating cortactin (SIRT1-cortatin-actin axis), and thereby maintaining actin cytoskeleton integrity.
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