炎症细胞因子和活性氧作为慢性肾脏病相关血管钙化的介质

Inflammatory cytokines and reactive oxygen species as mediators of chronic kidney disease-related vascular calcification.

作者信息

Agharazii Mohsen, St-Louis Ronald, Gautier-Bastien Alexandra, Ung Roth-Visal, Mokas Sophie, Larivière Richard, Richard Darren E

机构信息

Centre de recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Québec, QC, Canada; Département de médecine , Faculté de Médecine, Université Laval, Québec, QC, Canada;

Centre de recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Québec, QC, Canada;

出版信息

Am J Hypertens. 2015 Jun;28(6):746-55. doi: 10.1093/ajh/hpu225. Epub 2014 Nov 27.

DOI:10.1093/ajh/hpu225

PMID:25430697

Abstract

BACKGROUND

Vascular calcification, a regulated process in chronic kidney disease (CKD), requires vascular smooth muscle cell (VSMC) differentiation into osteoblast-like cells. This phenomenon can be enhanced by inflammatory cytokines and production of reactive oxygen species (ROS). In CKD rats with vascular calcification, we investigated whether inflammatory cytokines, ROS generation, and downstream signaling events are associated with CKD-related vascular calcification.

METHODS

CKD was induced in male Wistar rats by renal mass ablation and vascular calcification was induced with a high calcium-phosphate diet and vitamin D supplementation (Ca/P/VitD). At week 3-6, hemodynamic parameters were determined and thoracic aorta was harvested for assessment of vascular calcification, macrophage infiltration, cytokines expression, VSMC differentiation, ROS generation, and related signaling pathway activation.

RESULTS

CKD rats treated with Ca/P/VitD developed medial calcification of thoracic aorta and increased pulse pressure and aortic pulse wave velocity. VSMC differentiation was confirmed by increased bone morphogenetic protein-2 and osteocalcin expression and reduced α-smooth muscle actin expression. The expression of interleukin-1β, interleukin-6, and tumor necrosis factor were also increased. The expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p22(phox) and p47(phox) were increased, whereas the expression of antioxidant enzymes (SOD1, SOD2, Gpx1, and Prdx1) was reduced in CKD + Ca/P/VitD rats. Oxidized peroxiredoxin, a sensor of ROS generation, was significantly increased and ROS-sensitive signaling pathways were activated in the aorta from CKD + Ca/P/VitD rats.

CONCLUSION

This study demonstrates a relationship between inflammation/ROS and arterial calcification in CKD and contributes to understanding of the complex pathways that mediate arterial calcification in CKD patients.

摘要

背景

血管钙化是慢性肾脏病（CKD）中的一个受调控过程，需要血管平滑肌细胞（VSMC）分化为成骨样细胞。这种现象可被炎性细胞因子和活性氧（ROS）的产生所增强。在患有血管钙化的CKD大鼠中，我们研究了炎性细胞因子、ROS生成及下游信号事件是否与CKD相关的血管钙化有关。

方法

通过肾大部切除在雄性Wistar大鼠中诱导CKD，并通过高钙磷饮食和补充维生素D（Ca/P/VitD）诱导血管钙化。在第3至6周时，测定血流动力学参数，并采集胸主动脉以评估血管钙化、巨噬细胞浸润、细胞因子表达、VSMC分化、ROS生成及相关信号通路激活情况。

结果

接受Ca/P/VitD治疗的CKD大鼠出现胸主动脉中层钙化，脉压和主动脉脉搏波速度增加。通过骨形态发生蛋白-2和骨钙素表达增加以及α-平滑肌肌动蛋白表达降低证实了VSMC分化。白细胞介素-1β、白细胞介素-6和肿瘤坏死因子的表达也增加。在CKD + Ca/P/VitD大鼠中，烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶亚基p22（phox）和p47（phox）的表达增加，而抗氧化酶（SOD1、SOD2、Gpx1和Prdx1）的表达降低。氧化型过氧化物酶，一种ROS生成的传感器，在CKD + Ca/P/VitD大鼠的主动脉中显著增加，并且ROS敏感信号通路被激活。