Molecular mechanism of vascular calcification in chronic kidney disease

慢性肾脏病血管钙化的分子机制

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20390216/
• 关键词: 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

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脏疾病的患者中普遍存在。晚期糖基化终产物（RAGE）及其多种配体的受体与加速动脉粥样硬化的发病机理有关。方法和结果培养的大鼠和人主动脉平滑肌细胞（HASMC）被用表达愤怒的腺病毒转导。在这些细胞中，心肌素和SMC标记基因的表达显着抑制。有趣的是，在HASMC中，愤怒激活诱导碱性磷酸酶（ALP）表达，钙沉积和MSX2表达，这是成骨分化的关键转录因子。内源性分泌的愤怒显着抑制了愤怒引起的成骨分化。 RAGE诱导的ALP和MSX2表达被DAPT完全消除，DAPT是Notch信号通路的抑制剂。用骨形态发生蛋白2（BMP2）和愤怒信号在HASMC中协同诱导的MSX2和ALP的表达同时刺激。免疫组织化学表明，钙化的动脉粥样硬化斑块表达了愤怒，缺口成分和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.这些结果为愤怒轴在血管钙化中的作用提供了新的见解。

项目成果

Notch signaling regulates the differentiation of bone marrow-derived cells into smooth muscle-like cells during arterial lesion formation

• DOI: 10.1016/j.bbrc.2009.02.116
• 发表时间: 2009-04-17
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Doi, Hiroshi;Iso, Tatsuya;Kurabayashi, Masahiko
• 通讯作者: Kurabayashi, Masahiko

Activation of Receptor for advanced-glycation end products (RAGE) in duces Notch-Msx2-dependent osteoblastic, differentiation of vascular smooth muscle cells.

晚期糖基化终末产物 (RAGE) 受体的激活可导致血管平滑肌细胞的 Notch-Msx2 依赖性成骨细胞分化。

• 发表时间: 2008
• 作者: Toshihiro Suga;Tatsuya Iso;Takehisa Shimizu;Toru Tanaka;Sho-ichi Yamagishi;Masashi Arai;Tsutomu Imaizumi;Masahiko Kurabayashi
• 通讯作者: Masahiko Kurabayashi

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
• 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

Diabetes and Vascular Calcification

• DOI: 10.1007/978-981-10-4376-5_5
• 发表时间: 2018
• 作者: K. Mori;M. Inaba

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。

• 期刊: J.Atheroscler Thromb.(In Press.)
• 作者: Suga T;Iso T;Shimizu T;Tanka T;Yamagishi S;Takeuchi M;Imaizumi T;Kurabayashi M.
• 通讯作者: Kurabayashi M.