哺乳动物类雷帕霉素靶蛋白信号抑制可通过Klotho上调改善血管钙化

Mammalian target of rapamycin signaling inhibition ameliorates vascular calcification via Klotho upregulation
2015-10-28 09:48点击:255次发表评论
作者:Zhao, Y., Zhao, M.-M., Cai, Y., Zheng, M.-F., Sun, W.-L., Zhang, S.-Y., Kong, W., Gu, J., Wang, X. , Xu, M.-J.
机构: 分子心血管科学教育部重点实验室 健康科学中心 北京大学 基础医学院 生理及病理生理学系
期刊: KIDNEY INT2015年10月4期88卷

Vascular calcification (VC) is a major risk factor for cardiovascular mortality in chronic renal failure (CRF) patients, but the pathogenesis remains partially unknown and effective therapeutic targets should be urgently explored. Here we pursued the therapeutic role of rapamycin in CRF-related VC. Mammalian target of rapamycin (mTOR) signal was activated in the aortic wall of CRF rats. As expected, oral rapamycin administration significantly reduced VC by inhibiting mTOR in rats with CRF. Further in vitro results showed that activation of mTOR by both pharmacological agent and genetic method promoted, while inhibition of mTOR reduced, inorganic phosphate-induced vascular smooth muscle cell (VSMC) calcification and chondrogenic/osteogenic gene expression, which were independent of autophagy and apoptosis. Interestingly, the expression of Klotho, an antiaging gene that suppresses VC, was reduced in calcified vasculature, whereas rapamycin reversed membrane and secreted Klotho decline through mTOR inhibition. When mTOR signaling was enhanced by either mTOR overexpression or deletion of tuberous sclerosis 1, Klotho mRNA was further decreased in phosphate-treated VSMCs, suggesting a vital association between mTOR signaling and Klotho expression. More importantly, rapamycin failed to reduce VC in the absence of Klotho by using either siRNA knockdown of Klotho or Klotho knockout mice. Thus, Klotho has a critical role in mediating the observed decrease in calcification by rapamycin in vitro and in vivo.

 

通讯机构:Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, Health Science Center, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
学科代码:肾脏病学   关键词:哺乳动物类 雷帕霉素靶蛋白信号 ,中国作者重要发表 爱思唯尔医学网, Elseviermed
来源: Scopus
Scopus介绍:Scopus 于2004年11月正式推出,是目前全球规模最大的文摘和引文数据库。Scopus涵盖了由5000多家出版商出版发行的科技、医学和社会科学方面的18,000多种期刊,其中同行评审期刊16,500多种。相对于其他单一的文摘索引数据库而言,Scopus的内容更加全面,学科更加广泛,特别是在获取欧洲及亚太地区的文献方面,用户可检索出更多的文献数量。通过Scopus,用户可以检索到1823年以来的近4000万条摘要和题录信息,以及1996年以来所引用的参考文献。数据每日更新。 马上访问Scopus网站http://www.scopus.com/
顶一下(0
您可能感兴趣的文章
    发表评论网友评论(0)
      发表评论
      登录后方可发表评论,点击此处登录