IR@PKUHSC  > 北京大学基础医学院
学科主题基础医学
Mammalian target of rapamycin signaling inhibition ameliorates vascular calcification via Klotho upregulation
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
2015-10-01
DOI10.1038/ki.2015.160
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
WOS记录号WOS:000362219600012
引用统计
被引频次:19[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/65962
专题北京大学基础医学院
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
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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.
APA Zhao, Yang.,Zhao, Ming-Ming.,Cai, Yan.,Zheng, Ming-Fei.,Sun, Wei-Liang.,...&Xu, Ming-Jiang.(2015).Mammalian target of rapamycin signaling inhibition ameliorates vascular calcification via Klotho upregulation.KIDNEY INTERNATIONAL,88(4),711-721.
MLA Zhao, Yang,et al."Mammalian target of rapamycin signaling inhibition ameliorates vascular calcification via Klotho upregulation".KIDNEY INTERNATIONAL 88.4(2015):711-721.
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