尿毒症毒素硫酸盐对甲酚通过促糖化机制加剧心肌损伤和心力衰竭作用研究

Patients with chronic kidney disease (CKD) are at high risk of cardiovascular disease (CVD).Heart failure (HF) is the most common cause of CV mortality in the CKD population. However, the high prevalence of traditional cardiovascular risk factors (e.g. hypertension, diabetes, and dyslipidemia) does not fully explain this augmented cardiovascular risk. CKD is attributed to the progressive retention of a large number of compounds which, under normal conditions, are excreted by the healthy kidneys. These compounds are called uremic toxins when they interact negatively with biological functions. One uremic toxin, p-cresol sulfate (pCS), has been found to associate with cardiovascular mortality in clinical studies. However, the direct effect of pCS on cardiovascular system is still unclear. Our previous studies had found that pCS could significantly promote myocardial injury. Profound mechanism studies revealed that pCS has pro-glycation activity, indicate that pCS might have a deleterious impact on cardiovascular system through advanced glycation end products and their receptor (AGEs-RAGE) pathway. Based on these findings, we try future investigate the role of pCS in CKD-related myocardial injury and subsequent heart failure via in vitro and RAGE-knock out in vivo studies.

慢性肾病（CKD）患者常伴有较高心血管疾病（CVD）发生率，其中心力衰竭（HF）更是CKD的主要死因。但在CKD中多见的高血压、高脂血症、糖尿病等传统危险因素却不能完全解释这一现象。尿毒症毒素是因肾功能下降而特异潴留于CKD患者体内的代谢终产物，其中部分毒素因具有蛋白结合特性而无法通过常规透析治疗方法去除，其对心血管系统的潜在致病作用目前受到广泛关注。大量临床多因素回归分析已将焦点聚集在其中主要毒素- - 硫酸盐对甲酚（pCS）上，但其具体致病机制却仍不明确。我们的前期研究发现pCS具有促心肌损伤作用，深入机制研究初步证实pCS能够显著促进糖化，提示pCS的致病机制可能与促心肌损伤主要通路- - 终末糖化产物及其受体（AGEs-RAGE）相关。本项目拟通过体外细胞学实验及在体RAGE基因敲除研究，深入探讨pCS促心肌损伤并最终导致心力衰竭的具体致病机制，为临床改善治疗方案提供可靠理论依据。

慢性肾病（CKD）患者常伴有较高心血管疾病（CVD）发生率，其中心力衰竭（HF）更是CKD的主要死因。尿毒症毒素是因肾功能下降而特异潴留于CKD患者体内的代谢终产物，其对HF的潜在致病作用受到广泛关注。本课题主要将焦点聚集在主要毒素--硫酸盐对甲酚（PCS）上。本课题首先建立单侧肾切除（UNX）及5/6肾切除（Nx）小鼠模型，运用单次灌胃法研究PCS在正常对照、UNX、Nx小鼠体内的代谢动力学，成功建立单纯PCS干预小鼠模型。本课题后续通过在体动物实验证实，PCS干预小鼠心肌舒张功能显著减弱，对心肌标本行组织病理学检测发现PCS干预小鼠心肌细胞凋亡数量增高。本课题继而体外培养H9c2心肌细胞，流式检测以及蛋白免疫印迹均发现，PCS干预具有促心肌细胞凋亡作用，深入研究发现PCS的促凋亡作用与其促氧化应激机制相关。在临床研究中，本研究发现终末期肾衰病人左室舒张功能与其血浆中PCS浓度水平呈相关性。以上实验数据表明，尿毒症毒素PCS可通过促氧化应激作用，介导心肌细胞凋亡及纤维化，最终导致心功能不全。