Urea-induced ROS cause endothelial dysfunction in chronic renal failure.
Urea-induced ROS cause endothelial dysfunction in chronic renal failure.
复制标题
DOI：
10.1016/j.atherosclerosis.2015.01.034
复制
发表时间：
2015-04
期刊：
影响因子：
5.3
通讯作者：
Giardino I
中科院分区：
文献类型：
--
作者：
D'Apolito M;Du X;Pisanelli D;Pettoello-Mantovani M;Campanozzi A;Giacco F;Maffione AB;Colia AL;Brownlee M;Giardino I
慢性肾功能衰竭（CRF）患者加速动脉粥样硬化的致病因素尚不清楚。在这里，我们调查的假设，尿素浓度与CRF和增加ROS的生产在脂肪细胞也可能增加ROS生产直接在动脉内皮细胞，导致相同的病理生理变化与高血糖症。将人主动脉内皮细胞（HAEC）的原代培养物暴露于20 mM尿素48小时。C57 BL/6 J野生型小鼠进行5/6肾切除术或假手术。随机分组的5/6肾切除小鼠和它们的对照组也在最后的外科手术后立即开始用SOD/过氧化氢酶模拟物（MnTBAP）腹膜内注射15天。在CRF中看到的浓度的尿素诱导培养的HAEC中线粒体ROS的产生。尿素诱导的ROS通过抑制GAPDH引起内皮促炎途径的激活，包括蛋白激酶C亚型活性增加、己糖胺途径活性增加和细胞内AGEs（晚期糖基化终产物）积累。尿素诱导的ROS直接灭活抗动脉粥样硬化酶PGI 2合酶，也引起ER应激。正常化的线粒体ROS生产防止尿素的这些影响。在尿毒症小鼠中，MnTBAP治疗可预防主动脉氧化应激、PGI 2合酶活性降低和促炎蛋白TNFα、IL-6、VCAM 1、Endoglin和MCP-1表达增加。总之，这些数据表明，尿素本身，在CRF患者中常见的水平，导致内皮功能障碍和促动脉粥样硬化途径的激活。
The pathogenic events responsible for accelerated atherosclerosis in patients with chronic renal failure (CRF) are poorly understood. Here we investigate the hypothesis that concentrations of urea associated with CRF and increased ROS production in adipocytes might also increase ROS production directly in arterial endothelial cells, causing the same pathophysiologic changes seen with hyperglycemia. Primary cultures of human aortic endothelial cells (HAEC) were exposed to 20 mM urea for 48 hrs. C57BL/6J wild-type mice underwent 5/6 nephrectomy or a sham operation. Randomized groups of 5/6 nephrectomized mice and their controls were also injected i.p. with a SOD/catalase mimetic (MnTBAP) for 15 days starting immediately after the final surgical procedure. Urea at concentrations seen in CRF induced mitochondrial ROS production in cultured HAEC. Urea-induced ROS caused the activation of endothelial pro-inflammatory pathways through the inhibition of GAPDH, including increased protein kinase C isoforms activity, increased hexosamine pathway activity, and accumulation of intracellular AGEs (advanced glycation end products). Urea-induced ROS directly inactivated the anti-atherosclerosis enzyme PGI2 synthase and also caused ER stress. Normalization of mitochondrial ROS production prevented each of these effects of urea. In uremic mice, treatment with MnTBAP prevented aortic oxidative stress, PGI2 synthase activity reduction and increased expression of the pro-inflammatory proteins TNFα, IL-6, VCAM1, Endoglin, and MCP-1. Taken together, these data show that urea itself, at levels common in patients with CRF, causes endothelial dysfunction and activation of proatherogenic pathways.
登录
查看更多内容
影响因子：
19.6
作者：
Ivanovski, O;Szumilak, D;Massy, ZA
通讯作者：
Massy, ZA
影响因子：
15.9
作者：
D'Apolito, Maria;Du, Xueliang;Giardino, Ida
通讯作者：
Giardino, Ida
影响因子：
3.9
作者：
Day, BJ;Fridovich, I;Crapo, JD
通讯作者：
Crapo, JD
影响因子：
15.9
作者：
Harja, Evis;Bu, De-Xiu;Schmidt, Ann Marie
通讯作者：
Schmidt, Ann Marie
影响因子：
15.9
作者：
SCHMIDT, AM;HORI, O;STERN, D
通讯作者：
STERN, D