High phosphate impairs arterial endothelial function through AMPK-related pathways in mouse resistance arteries
High phosphate impairs arterial endothelial function through AMPK-related pathways in mouse resistance arteries
复制标题
高磷酸盐通过小鼠阻力动脉中 AMPK 相关途径损害动脉内皮功能
DOI：
10.1111/apha.13595
复制
发表时间：
2020-12-20
影响因子：
6.3
通讯作者：
Lai, En Yin
中科院分区：
文献类型：
--
作者：
Hu, Weipeng;Jiang, Shan;Lai, En Yin
目的在肾脏疾病患者中，高血磷与心血管风险有关。我们推测高磷(HP)通过内皮损伤了动脉血管扩张，并探讨了可能的潜在机制。方法观察HP饮食小鼠的离体血管松弛、内皮功能、肾小球滤过率(GFR)、氧化应激状态和蛋白表达。结果高磷(1.3%)饮食12周后，肠系膜动脉、肾小叶间动脉和传入小动脉内皮细胞的内皮依赖性舒张功能受损，肾小球滤过率降低，急性给予乙酰胆碱后血压下降。Hp饮食小鼠肠系膜动脉内皮细胞PPARα/LKB1/AMPK/eNOS通路减弱。PPARα激动剂WY-14643可改善肠系膜动脉的舒张性损伤。磷酸盐转运体PIT-1基因敲除可阻止HUVECs中磷的内流，从而阻止HP对eNOS活性的抑制。HP饮食小鼠血管内皮细胞、胞浆和线粒体活性氧(ROS)增加。此外，幽门螺杆菌还降低了线粒体相关抗氧化基因的表达。结论幽门螺杆菌通过降低eNOS活性和增加线粒体ROS来降低NO的生物利用度，从而降低内皮细胞的功能，其中AMPK相关的信号转导通路可能起关键作用。
Aims In patients with renal disease, high serum phosphate shows a relationship with cardiovascular risk. We speculate that high phosphate (HP) impairs arterial vasodilation via the endothelium and explore potential underlying mechanisms.Methods Isolated vessel relaxation, endothelial function, glomerular filtration rate (GFR), oxidative stress status and protein expression were assessed in HP diet mice. Mitochondrial function and protein expression were assessed in HP-treated human umbilical vein endothelial cells (HUVECs).Results High phosphate (1.3%) diet for 12 weeks impaired endothelium-dependent relaxation in mesenteric arteries, kidney interlobar arteries and afferent arterioles; reduced GFR and the blood pressure responses to acute administration of acetylcholine. The PPAR alpha/LKB1/AMPK/eNOS pathway was attenuated in the endothelium of mesenteric arteries from HP diet mice. The observed vasodilatory impairment of mesenteric arteries was ameliorated by PPAR alpha agonist WY-14643. The phosphate transporter PiT-1 knockdown prevented HP-mediated suppression of eNOS activity by impeding phosphorus influx in HUVECs. Endothelium cytoplasmic and mitochondrial reactive oxygen species (ROS) were increased in HP diet mice. Moreover HP decreased the expression of mitochondrial-related antioxidant genes. Finally, mitochondrial membrane potential and PGC-1 alpha expression were reduced by HP treatment in HUVECs, which was partly restored by AMPK alpha agonist.Conclusions HP impairs endothelial function by reducing NO bioavailability via decreasing eNOS activity and increasing mitochondrial ROS, in which the AMPK-related signalling pathways may play a key role.