Hesse Bettina, Rovas Alexandros, Buscher Konrad, Kusche-Vihrog Kristina, Brand Marcus, Di Marco Giovana Seno, Kielstein Jan T, Pavenstädt Hermann, Linke Wolfgang A, Nofer Jerzy-Roch, Kümpers Philipp, Lukasz Alexander
Department of Medicine D, Division of General Internal Medicine, Nephrology, and Rheumatology, University Hospital Münster, Münster, Germany; Institute of Physiology II, University Hospital Münster, Münster, Germany.
Department of Medicine D, Division of General Internal Medicine, Nephrology, and Rheumatology, University Hospital Münster, Münster, Germany.
Kidney Int. 2020 Mar;97(3):502-515. doi: 10.1016/j.kint.2019.10.017. Epub 2019 Nov 13.
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.
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等方式，使其组成向具有内皮损伤表型的方向发生改变。内皮糖萼是一层富含碳水化合物的内膜表面衬里层，是抵御包括动脉粥样硬化在内的血管疾病的第一道防线。在此，我们进行了一项转化性横断面研究，以确定d-HDL中的对称二甲基精氨酸作为糖萼损伤介质的作用。使用共聚焦显微镜和原子力显微镜，发现来自健康供体的完整HDL可维持糖萼，而来自血液透析患者的分离HDL和外源性对称二甲基精氨酸会在体外以剂量依赖的方式对内皮细胞中的糖萼造成显著损伤。对称二甲基精氨酸通过Toll样受体2和基质金属蛋白酶-9介导的分子途径引发糖萼退化。相应的活体显微镜检查显示，外源性对称二甲基精氨酸和血液透析患者的d-HDL会导致糖萼分解，随后导致白细胞滚动改变。如文献所述，根据循环HDL胆固醇和对称二甲基精氨酸计算出估计HDL功能的生物活性HDL。生物活性HDL是唯一能够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病中的糖萼分解。
