Molecular mechanism of vascular calcification in chronic kidney disease

慢性肾脏病血管钙化的分子机制

基本信息

批准号：
20390216
负责人：
KURABAYASHI Masahiko
金额：
$ 12.23万
依托单位：
Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

项目摘要

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.

背景-血管钙化在糖尿病和慢性肾病患者中普遍存在。晚期糖基化终产物受体(RAGE)及其多种配体与加速动脉粥样硬化的发病机制有关。方法和结果-用表达RAGE的腺病毒转导培养的大鼠和人主动脉平滑肌细胞(HASMC)。这些细胞中心肌素和 SMC 标记基因的表达受到显着抑制。有趣的是，RAGE 激活诱导 HASMC 中碱性磷酸酶 (ALP) 表达、钙沉积和 Msx2 表达，Msx2 表达是成骨分化的关键转录因子。 RAGE诱导的成骨分化被内源性分泌RAGE显着抑制。 RAGE 诱导的 ALP 和 Msx2 表达被 Notch 信号通路抑制剂 DAPT 完全消除。同时刺激骨形态发生蛋白 2 (BMP2) 和 RAGE 信号协同诱导 HASMC 中 Msx2 和 ALP 的表达。免疫组织化学显示人钙化动脉粥样硬化斑块表达RAGE、Notch成分和Msx2。人血清在 RAGE 过表达的 HASMC 中诱导的 ALP 活性与血清肌酐水平呈正相关，但与磷酸盐和血红蛋白 A1c 水平无关。结论-这些结果表明，RAGE 的激活不仅抑制心肌素依赖性 SMC 基因表达，而且还抑制心肌素依赖的 SMC 基因表达。通过 Notch/Msx2 诱导诱导血管 SMC 成骨分化。这些结果为 RAGE 轴在血管钙化中的作用提供了新的见解。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Activation of receptor for AGE induces osteogenic differentiation of vascular smooth muscle cells.

AGE 受体的激活诱导血管平滑肌细胞的成骨分化。

DOI：
发表时间：
期刊：
J.Atheroscler Thromb.(In Press.)
影响因子：
0
作者：
Suga T;Iso T;Shimizu T;Tanka T;Yamagishi S;Takeuchi M;Imaizumi T;Kurabayashi M.
通讯作者：
Kurabayashi M.

Diabetes and Vascular Calcification

DOI：
10.1007/978-981-10-4376-5_5
发表时间：
2018
期刊：
影响因子：
0
作者：
K. Mori;M. Inaba
通讯作者：
K. Mori;M. Inaba

PIAS1 mediates TGFbeta-induced SM alpha-actin gene expression through inhibition of KLF4 function-expression by protein sumoylation.

DOI：
10.1161/atvbaha.108.172700
发表时间：
2009-01
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Kawai-Kowase K;Ohshima T;Matsui H;Tanaka T;Shimizu T;Iso T;Arai M;Owens GK;Kurabayashi M
通讯作者：
Kurabayashi M

Runx2 represses myocardin-mediated differentiation and facilitates osteogenic conversion of vascular smooth muscle cells