| Project/Area Number |
20390216
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Gunma University |
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Principal Investigator |
KURABAYASHI Masahiko Gunma University, 大学院・医学系研究科, 教授 (00215047)
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| Co-Investigator(Kenkyū-buntansha) |
ARAI Masashi 群馬大学, 大学院・医学系研究科, 准教授 (60270857)
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| Project Period (FY) |
2008 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥19,110,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥4,410,000)
Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2009: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2008: ¥13,390,000 (Direct Cost: ¥10,300,000、Indirect Cost: ¥3,090,000)
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| Keywords | 骨芽細胞 / 血管石灰化 / 血管平滑筋細胞 / Notch / AGE / 慢性腎不全 / FGF23 / Klotho / 細胞分化 / 転写因子 / 糖尿病 / 腎不全 / 遺伝子発現 / 動脈硬化 / 血管生物学 / 遺伝子 / 慢性腎臓病 / Notchシグナル / 骨形成 |
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| Research Abstract |
Background-Vascular calcification is prevalent in patients with diabetes and chronic kidney disease. Receptor for advanced glycation end products (RAGE) and its multiple ligands have been implicated in the pathogenesis of accelerated atherosclerosis.
Methods and Results-Cultured rat and human aortic smooth muscle cells (HASMC) were transduced with adenovirus expressing RAGE. Expression of myocardin and the SMC-marker genes was significantly repressed in these cells. Interestingly, RAGE activation induced alkaline phosphatase (ALP) expression, calcium deposition, and Msx2 expression, a crucial transcription factor for osteogenic differentiation, in HASMC. RAGE-induced osteogenic differentiation was significantly inhibited by endogenous secretory RAGE. RAGE-induced ALP and Msx2 expression was completely abrogated by DAPT, an inhibitor for Notch signaling pathway. Simultaneous stimulation with bone morphogenetic protein 2 (BMP2) and RAGE signaling synergistically induced expression of Msx2 and ALP in HASMC. Immunohistochemistry revealed that the human calcifying atherosclerotic plaque expressed RAGE, Notch components and Msx2. The ALP activity induced in RAGE-overexpressing HASMCs by human serum was positively correlated with serum creatinine level, but not with phosphate and hemoglobin A1c levels.Conclusions-These results indicate that activation of RAGE not only inhibits myocardin-dependent SMC gene expression, but also induces osteogenic differentiation of vascular SMC through Notch/Msx2 induction. These results provide the novel insight into a role of RAGE axis in vascular calcification.
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