| Project/Area Number |
18K16015
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53040:Nephrology-related
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| Research Institution | Kawasaki Medical School |
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Principal Investigator |
Nagasu Hajime 川崎医科大学, 医学部, 講師 (40412176)
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 糖尿病性腎臓病 / インフラマソーム / 上皮細胞 / kidney / mitochondoria / inflammasome / Inflammasome / podocyte / 糖尿病性腎症 |
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| Outline of Final Research Achievements |
Diabetic kidney disease (DKD) is one of the common vascular complications of diabetes mellitus. Nitric oxide (NO) produced in the endothelial cells by endothelial nitric oxide synthase (eNOS) is an important mediator for the maintenance of vascular homeostasis. While it is well known that inflammation is important pathways in the development of DKD.
To determine the role of inflammasome on the development of glomerulopathy, we generated eNOS-ASC double knockout mice (eNOS-ASC-DKO). urinary albumin excretions were increased much more in eNOS/STZ than in WT/STZ, while the glomeruli were more damaged in eNOSKO/STZ than in WT/STZ. Urinary albumin excretion was lower in eNOS-ASC-DKO/STZ compared with eNOSKO/STZ. In eNOS-deficient mice, inflammasomes were activated, and glomerular injuries were exacerbated. However in eNOS-ASC-STZ mice, the glomerular damage were attenuated. Our data suggested that eNOS/NO signaling ameliorates podocytes via the regulation of inflammasome activation in DKD.
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| Academic Significance and Societal Importance of the Research Achievements |
内皮機能障害では糸球体硬化病変を加速させうることが示された。これは臨床的に重要な知見でありその機序解明は病態解明の大きな課題であった。本研究では糸球体内の慢性炎症制御の破綻が重要であることが示された。現在の動脈硬化関連疾患に付随する腎疾患共通のメカニズムとして特にInflammasome活性化の制御が重要であり、今後はこれらをターゲットとした治療薬の開発が望まれる。また、既存薬剤による効果を検討し早期の臨床応用を目指す。特にNO下流のPDE阻害薬もしくはsGC活性化薬の有効性を検討していきたい。
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