Mitochondrial reactive oxygen species promote p65 nuclear translocation mediating high-phosphate-induced vascular calcification in vitro and in vivo

被引:182
作者
Zhao, Ming-Ming [1 ]
Xu, Ming-Jiang [1 ]
Cai, Yan [1 ]
Zhao, Gexin [1 ]
Guan, Youfei [1 ]
Kong, Wei [1 ]
Tang, Chaoshu [1 ]
Wang, Xian [1 ]
机构
[1] Peking Univ, Key Lab Mol Cardiovasc Sci, Dept Physiol & Pathophysiol, Sch Basic Med Sci,Hlth Sci Ctr,Minist Educ, Beijing 100191, Peoples R China
基金
中国国家自然科学基金;
关键词
chronic renal failure; hyperphosphatemia; NF-kappa B; oxidative stress; phenotypic transition; STAGE RENAL-DISEASE; SMOOTH-MUSCLE-CELL; NF-KAPPA-B; ARTERY CALCIFICATION; OXIDATIVE STRESS; CORONARY-ARTERY; DOWN-REGULATION; UREMIC RATS; DIFFERENTIATION; DIALYSIS;
D O I
10.1038/ki.2011.18
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Hyperphosphatemia is the major risk factor associated with vascular calcification (VC) in end-stage renal disease. As oxidative stress is increased in uremia, we studied the role of mitochondrial reactive oxygen species (ROS) and nuclear factor-kappa B signaling in phosphate-induced VC. In an in vitro calcification model (beta-glycerophosphate (BGP) induction) using bovine aortic smooth muscle cells, the production of intracellular and mitochondrial ROS, or superoxide anion, was stimulated by increased mitochondrial membrane potential. This effect was blocked by the superoxide dismutase (SOD) mimic MnTMPyP, a respiratory chain inhibitor rotenone, or a protonophore. Calcium deposition and the switch of smooth muscle cells from a contractile to an osteogenic phenotype were decreased when mitochondrial ROS generation was inhibited by the respiratory chain inhibitor, MnTMPyP, or the overexpression of SOD1 and SOD2 and uncoupling protein 2. The phosphorylation of IkK beta, I kappa B alpha degradation, and p65 nuclear translocation were increased by BGP but reversed when mitochondrial ROS production was blocked by protonophore or MnTMPyP. Knockdown of endogenous p65 or overexpression of I kappa B alpha reduced calcium deposition in the cultured cells. Furthermore, in a rat model of dietary adenine-induced chronic renal failure, MnTMPyP reduced aortic ROS levels, p65 activation, and calcium deposition. Thus, mitochondrial ROS-mediated p65 nuclear translocation is involved in phosphate-induced VC. Kidney International (2011) 79, 1071-1079; doi:10.1038/ki.2011.18; published online 2 March 2011
引用
收藏
页码:1071 / 1079
页数:9
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