| Project/Area Number |
16K15472
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Kidney internal medicine
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| Research Institution | Kanazawa Medical University |
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Principal Investigator |
KOYA Daisuke 金沢医科大学, 医学部, 教授 (70242980)
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| Co-Investigator(Kenkyū-buntansha) |
金崎 啓造 金沢医科大学, 医学部, 准教授 (60589919)
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| Research Collaborator |
TAKAGAKI Yuta
KITADA Munehiro
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 内皮細胞 / オートファジー / 線維化 / 高脂肪食負荷 / 腎臓 / 心臓 / 内皮間葉化 / IL-6 / 内皮・間葉化 / 腎線維化 / 心線維化 / 膵島 / 内皮 / 内皮間葉転化 / 上皮間葉転化 / 糖尿病 / 内皮・間葉転化 / 血管内皮細胞 |
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| Outline of Final Research Achievements |
Inhibition of autophagy, either by a specific inhibitor or siRNA for Atg5, in human microvascular endothelial cells (HMVECs) induced EndMT. The IL-6 level was significantly higher in Atg5 siRNA-transfected HMVEC culture medium compared with the control HMVEC culture medium, and neutralization of IL-6 by a specific antibody completely inhibited EndMT in Atg5 siRNA transfected HMVECs. Similar to the in vitro data, endothelial-specific Atg5 knockout mice (Atg5endo; Cdh5-Cre Atg5flox/flox mice) displayed both EndMT-associated kidney and heart fibrosis when compared to littermate controls. The plasma level of IL-6 was higher in Atg5endo mice compared to that of control mice, and fibrosis was accelerated in Atg5endo mice treated with HFD; neutralization of IL-6 by a specific antibody inhibited EndMT and fibrosis in HFD-fed Atg5endo mice associated with the amelioration of metabolic defects.
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| Academic Significance and Societal Importance of the Research Achievements |
ヒト血管内皮細胞におけるオートファージーが生理学的意義として恒常性維持に重要であることを明らかにできた。さらに、高脂肪食負荷オートファージー不全マウスにおいて、腎・心線維化を生じ、それがIL-6中和抗体にて改善されたことは、2型糖尿病性腎臓病および肥満関連腎症に、すでに関節リウマチの治療薬として臨床応用されているIL-6阻害薬が有効な治療戦略になりえる可能性を示唆する。
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