Graduate Institute of Clinical Medicine, College of Medicines, Kaohsiung Medical University, Kaohsiung, Taiwan.
Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Sci Rep. 2021 Feb 15;11(1):3786. doi: 10.1038/s41598-021-83383-x.
Protein-bound uremic toxins (Indoxyl sulfate [IS] and p-cresyl sulfate [PCS]) are both associated with cardiovascular (CV) and all-cause mortality in subjects with chronic kidney disease (CKD). Possible mechanisms have not been elucidated. In hemodialysis patients, we investigated the relationship between the free form of IS and PCS and 181 CV-related proteins. First, IS or PCS concentrations were checked, and high levels were associated with an increased risk of acute coronary syndrome (ACS) in 333 stable HD patients. CV proteins were further quantified by a proximity extension assay. We examined associations between the free form protein-bound uremic toxins and the quantified proteins with correction for multiple testing in the discovery process. In the second step, the independent association was evaluated by multivariable-adjusted models. We rank the CV proteins related to protein-bound uremic toxins by bootstrapped confidence intervals and ascending p-value. Six proteins (signaling lymphocytic activation molecule family member 5, complement component C1q receptor, C-C motif chemokine 15 [CCL15], bleomycin hydrolase, perlecan, and cluster of differentiation 166 antigen) were negatively associated with IS. Fibroblast growth factor 23 [FGF23] was the only CV protein positively associated with IS. Three proteins (complement component C1q receptor, CCL15, and interleukin-1 receptor-like 2) were negatively associated with PCS. Similar findings were obtained after adjusting for classical CV risk factors. However, only higher levels of FGF23 was related to increased risk of ACS. In conclusion, IS and PCS were associated with several CV-related proteins involved in endothelial barrier function, complement system, cell adhesion, phosphate homeostasis, and inflammation. Multiplex proteomics seems to be a promising way to discover novel pathophysiology of the uremic toxin.
蛋白结合型尿毒症毒素（硫酸吲哚酚[IS]和对甲酚硫酸盐[PCS]）与慢性肾脏病（CKD）患者的心血管（CV）和全因死亡率均相关。但可能的机制尚未阐明。在血液透析患者中，我们研究了 IS 和 PCS 游离形式与 181 种与 CV 相关的蛋白之间的关系。首先，检查了 IS 或 PCS 浓度，在 333 例稳定 HD 患者中，高水平 IS 或 PCS 与急性冠状动脉综合征（ACS）风险增加相关。通过邻近延伸测定进一步定量 CV 蛋白。我们在发现过程中通过多重检验校正，检查了游离型蛋白结合型尿毒症毒素与定量蛋白之间的关联。在第二步中，通过多变量调整模型评估了独立关联。我们通过 bootstrap 置信区间和升序 p 值对与蛋白结合型尿毒症毒素相关的 CV 蛋白进行排名。有 6 种蛋白（信号淋巴细胞激活分子家族成员 5、补体成分 C1q 受体、C-C 基序趋化因子 15[CCL15]、博来霉素水解酶、硫酸乙酰肝素和分化簇 166 抗原）与 IS 呈负相关。成纤维细胞生长因子 23[FGF23]是唯一与 IS 呈正相关的 CV 蛋白。有 3 种蛋白（补体成分 C1q 受体、CCL15 和白细胞介素 1 受体样 2）与 PCS 呈负相关。在调整了经典 CV 危险因素后，也得到了相似的发现。但是，只有更高水平的 FGF23 与 ACS 风险增加相关。总之，IS 和 PCS 与几种与 CV 相关的蛋白相关，这些蛋白涉及内皮屏障功能、补体系统、细胞黏附、磷酸盐稳态和炎症。多重蛋白质组学似乎是发现尿毒症毒素新病理生理学的一种很有前途的方法。
