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Symmetric dimethylarginine in dysfunctional high-density lipoprotein mediates endothelial glycocalyx breakdown in chronic kidney disease.
Kidney International ( IF 14.8 ) Pub Date : 2019-11-13 , DOI: 10.1016/j.kint.2019.10.017
Bettina Hesse 1 , Alexandros Rovas 2 , Konrad Buscher 2 , Kristina Kusche-Vihrog 3 , Marcus Brand 2 , Giovana Seno Di Marco 2 , Jan T Kielstein 4 , Hermann Pavenstädt 2 , Wolfgang A Linke 5 , Jerzy-Roch Nofer 6 , Philipp Kümpers 2 , Alexander Lukasz 2
Affiliation  

Dysfunctional high-density lipoprotein (d-HDL) in chronic kidney disease is known to have a change in composition towards an endothelial-damaging phenotype, amongst others, via the accumulation of symmetric dimethylarginine. The endothelial glycocalyx, a carbohydrate-rich layer lining the endothelial luminal surface, is a first line defense against vascular diseases including atherosclerosis. Here we conducted a translational, cross-sectional study to determine the role of symmetric dimethylarginine in d-HDL as a mediator of glycocalyx damage. Using confocal and atomic force microscopy, intact HDL from healthy donors was found to maintain the glycocalyx while isolated HDL from hemodialysis patients and exogenous symmetric dimethylarginine caused significant damage to the glycocalyx in endothelial cells in vitro in a dose-dependent manner. Symmetric dimethylarginine triggered glycocalyx deterioration via molecular pathways mediated by toll-like-receptor 2 and matrix metalloprotease-9. Corresponding intravital microscopy revealed that exogenous symmetric dimethylarginine and d-HDL from hemodialysis patients caused glycocalyx breakdown, which subsequently contributed to alterations in leukocyte rolling. Biologically effective HDL, which estimates the functionality of HDL, was calculated from circulating HDL-cholesterol and symmetric dimethylarginine, as described in the literature. Biologically effective HDL was the only parameter that could independently predict glycocalyx damage in vivo. Thus, our data suggest that symmetric dimethylarginine in d-HDL mediates glycocalyx breakdown in chronic kidney disease.

中文翻译:

功能失调的高密度脂蛋白中对称的二甲基精氨酸介导慢性肾脏疾病中的内皮糖萼分解。

已知慢性肾脏病中功能失调的高密度脂蛋白(d-HDL)会通过对称二甲基精氨酸的积累而朝着内皮破坏表型改变成分。内皮糖萼是衬在内皮腔表面的富含碳水化合物的一层,是抵抗包括动脉粥样硬化在内的血管疾病的一线防御。在这里,我们进行了翻译,横断面研究,以确定对称的二甲基精氨酸在d-HDL中作为糖萼受损介质的作用。使用共聚焦和原子力显微镜,发现来自健康供体的完整HDL可以维持糖萼,而从血液透析患者和外源对称二甲基精氨酸中分离得到的HDL则在体外以剂量依赖的方式对内皮细胞中的糖萼造成了重大损害。对称的二甲基精氨酸通过toll样受体2和基质金属蛋白酶9介导的分子途径触发糖萼降解。相应的活体显微镜检查显示,血液透析患者的外源对称二甲基精氨酸和d-HDL引起糖萼分解,继而导致白细胞滚动改变。如文献所述,从循环的HDL-胆固醇和对称的二甲基精氨酸计算出可评估HDL功能的生物有效HDL。生物学有效的HDL是唯一可以独立预测体内糖萼损伤的参数。因此,我们的数据表明,d-HDL中的对称二甲基精氨酸介导了慢性肾脏疾病中糖萼的分解。
更新日期:2019-11-13
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