Repair and regeneration of proximal tubular cells by inhibiting proxyl hydroxylases
Project/Area Number |
20K08626
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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 | Tohoku University (2021-2022) The University of Tokyo (2020) |
Principal Investigator |
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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Keywords | 低酸素 / プロリン水酸化酵素 / 低酸素誘導因子 / AKI-CKD移行 / 虚血再灌流障害 / 慢性腎臓病 |
Outline of Research at the Start |
尿細管間質の慢性低酸素状態は、慢性腎臓病(CKD)の病態進展因子である。従来、急性腎障害(AKI)は一過性の病態であると考えられてきたが、近年、長期経過において高頻度にCKDを発症することが明らかになった。CKDへの移行には内皮細胞障害に伴う尿細管間質の微小循環不全が関与するため、低酸素誘導因子(HIF)の活性化が病態の改善をもたらす可能性があある。本研究では当仮設の検証を行う。
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Outline of Final Research Achievements |
This study investigated a possible role of HIF1 in proximal tubules in a AKI-CKD transition model. Tamoxifen- inducible, proximal tubular- specific prolyl hydroxylase knockout (Ndrg1-CreERT2/Phd1,2,3cKO) mice were subjected to bilateral ischemia-reperfusion injury (IRI). Tamoxifen was given in the recovery phase to activate HIF1, and histological analyses were carried out at day 28. In the tamoxifen-treated group (IRI/Tam+), serum creatinine levels and albuminuria were significantly lower than the control (IRI/Tam-) group, and renal fibrosis was less severe. Mechanistically, the number of Ki-67- positive, proliferating proximal tubular cells was larger in the IRI/Tam+ group, and there was an increase in phosphorylated histone H3. These findings suggest that proximal tubular HIF1 contributes to ameliorating AKI-CKD transition by facilitating proliferation of tubular epithelial cells and reducing the production of inflammatory cytokines and fibrotic factors in the G2/M cells.
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Academic Significance and Societal Importance of the Research Achievements |
AKIは古典的には短時間で急激に腎機能が低下する一過性の病態と考えられてきたが、近年の疫学研究によって、AKIはCKDへの移行リスクが高く、末期腎不全リスクも3.1倍高まることが明らかになった。しかしながら本病態に対して確立された治療法は存在しない。本研究の成果は上記のAKI-CKD移行に対して、近位尿細管における低酸素誘導因子HIF1の活性化が障害軽減をもたらす可能性を示唆しており、将来の新規治療法の開発や実効的な医療介入につながることが期待される。
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Report
(4 results)
Research Products
(56 results)
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[Journal Article] Effect of M2-like macrophages of the injured-kidney cortex on kidney cancer progression2022
Author(s)
Taisuke Ishii, Imari Mimura, Koji Nagaoka, Akihiro Naito, Takehito Sugasawa, Ryohei Kuroda, Daisuke Yamada, Yasuharu Kanki, Haruki Kume, Tetsuo Ushiku, Kazuhiro Kakimi, Tetsuhiro Tanaka, Masaomi Nangaku
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Journal Title
Cell Death Discovery
Volume: 5
Issue: 1
Pages: 480-480
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Conditions, pathogenesis, and progression of diabetic kidney disease and early decliner in Japan2020
Author(s)
Yoshida Y, Kashiwabara K, Hirakawa Y, Tanaka T, Noso S, Ikegami H, Ohsugi M, Ueki K, Mita T, Watada H, Koya D, Mise K, Wada J, Shimizu M, Wada T, Ito Y, Narita I, Kashihara N, Nangaku M, Matsuyama Y
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Journal Title
BMJ Open Diabetes Research & Care
Volume: 8
Issue: 1
Pages: 1-8
DOI
Related Report
Peer Reviewed / Open Access
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