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学科主题: 基础医学
题名:
Mammalian target of rapamycin signaling inhibition ameliorates vascular calcification via Klotho upregulation
作者: Zhao, Yang1,2; Zhao, Ming-Ming1,2; Cai, Yan1,2; Zheng, Ming-Fei3; Sun, Wei-Liang1,2; Zhang, Song-Yang1,2; Kong, Wei1,2; Gu, Jun4; Wang, Xian1,2; Xu, Ming-Jiang1,2
关键词: aging ; chronic renal failure ; inorganic phosphate ; vascular smooth muscle cell
刊名: KIDNEY INTERNATIONAL
发表日期: 2015-10-01
DOI: 10.1038/ki.2015.160
卷: 88, 期:4, 页:711-721
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Urology & Nephrology
研究领域[WOS]: Urology & Nephrology
关键词[WOS]: MUSCLE-CELL CALCIFICATION ; CHRONIC KIDNEY-DISEASE ; CHRONIC-RENAL-FAILURE ; LIFE-SPAN ; OSTEOBLASTIC DIFFERENTIATION ; STEM-CELLS ; PHOSPHATE ; PROTEIN ; ACTIVATION ; EXPRESSION
英文摘要:

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.

语种: 英语
所属项目编号: 81270370 ; 81470557 ; 81170099 ; 7112083 ; 2011CB503904 ; 2012CB518002 ; 2012BAI39B03
项目资助者: National Natural Science Foundation of China ; Beijing Natural Science Foundation ; National Basic Research Program of China ; National Science &amp ; Technology Pillar Program
WOS记录号: WOS:000362219600012
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内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/65962
Appears in Collections:基础医学院_期刊论文

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作者单位: 1.Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Beijing 100191, Peoples R China
2.Minist Educ, Key Lab Mol Cardiovasc Sci, Beijing, Peoples R China
3.Beijing 6 Hosp, Dept Surg, Beijing, Peoples R China
4.Peking Univ, State Key Lab Prot & Plant Gene Res, Beijing 100191, Peoples R China

Recommended Citation:
Zhao, Yang,Zhao, Ming-Ming,Cai, Yan,et al. Mammalian target of rapamycin signaling inhibition ameliorates vascular calcification via Klotho upregulation[J]. KIDNEY INTERNATIONAL,2015,88(4):711-721.
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