Vascular calcification and inorganic phosphate
Vascular calcification and inorganic phosphate
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DOI：
10.1053/ajkd.2001.27394
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发表时间：
2001-10-01
影响因子：
13.2
通讯作者：
Morii, H
中科院分区：
文献类型：
--
作者：
Giachelli, CM;Jono, S;Morii, H
尿毒症患者的血管钙化与血清磷酸盐水平升高高度相关。为了阐明这一过程，我们检查了细胞外无机磷酸盐 (Pi) 水平在体外调节人主动脉平滑肌细胞 (HSMC) 培养物矿化的能力。当在含有正常生理水平 Pi (1.4 mmol/L Pi) 的培养基中培养时，HSMC 以单层生长并且不矿化。相比之下，在 Pi 水平与高磷血症个体 (>1.4 mmol/L) 相当的培养基中培养的 HSMC，显示出细胞培养物钙沉积的剂量依赖性增加。机制研究表明，HSMC 的 Pi 升高处理还增强了成骨标志物、骨钙素和 Cbfa-1 的表达。 Pi 升高对 HSMC 的影响是由钠依赖性磷酸盐协同转运蛋白 (NPC) 介导的，具体的 NPC 抑制剂膦甲酸 (PFA) 能够剂量依赖性地抑制 Pi 诱导的钙沉积以及骨钙素和 Cbfa-1 基因表达。使用聚合酶链反应和Northern印迹分析，HSMC中的NPC被鉴定为Pit-1（Glvr-1），是III型NPC的成员。有趣的是，血小板源性生长因子-BB（PDGF-BB）是一种有效的致动脉粥样硬化刺激物，它增加了磷酸盐摄取的最大速度（Vmax），但没有增加磷酸盐摄取的亲和力（Km），增强了Pit-1 mRNA的表达，并以时间和剂量依赖性方式诱导HSMC培养物钙化。重要的是，在存在 PDGF 的情况下，HSMC 培养物钙化发生在正常磷血症条件下。这些数据表明，升高的 Pi 可能直接刺激 HSMC 发生易于钙化的表型变化，并可能有助于解释高磷血症条件下人类转移性钙化的现象以及富含 PDGF 的动脉粥样硬化病变中钙化增加的现象。 (C) 2001 年，国家肾脏基金会 (National Kidney Foundation, Inc.)
Vascular calcification is highly correlated with elevated serum phosphate levels in uremic patients. To shed light an this process, we examined the ability of extracellular inorganic phosphate (Pi) levels to regulate human aortic smooth muscle cell (HSMC) culture mineralization in vitro. When cultured in media containing normal physiological levels of Pi (1.4 mmol/L Pi), HSMC grew in monolayers and did not mineralize. In contrast, HSMC cultured in media containing Pi levels comparable to those seen in hyperphosphatemic individuals (>1.4 mmol/L), showed dose-dependent increases in cell culture calcium deposition. Mechanistic studies showed that elevated Pi treatment of HSMC also enhanced the expression of the osteogenic markers, osteocalcin and Cbfa-1. The effects of elevated Pi on HSMC were mediated by a sodium-dependent phosphate cotransporter (NPC), as Indicated by the ability of the specific NPC inhibitor, phosphonoformic acid (PFA), to dose-dependently inhibit Pi-Induced calcium deposition as well as osteocalcin and Cbfa-1 gene expression. Using polymerase chain reaction and Northern blot analyses, the NPC in HSMC was Identified as Pit-1 (Glvr-1), a member of the type III NPCs. Interestingly, platelet-derived growth factor-BB (PDGF-BB), a potent atherogenic stimulus, Increased the maximum velocity (Vmax) but not the affinity (Km) of phosphate uptake, enhanced the expression of Pit-1 mRNA, and induced HSMC culture calcification in a time- and dose-dependent manner. Importantly, in the presence of PDGF, HSMC culture calcification occurred under normophosphatemic conditions. These data suggest that elevated Pi may directly stimulate HSMC to undergo phenotypic changes that predispose to calcification and may help explain both the phenomena of human metastatic calcification under hyperphosphatemic conditions as well as increased calcification in PDGF-rich atherosclerotic lesions. (C) 2001 by the National Kidney Foundation, Inc.