尿毒症毒素硫酸盐对甲酚通过促糖化效应致心脏舒张功能不全及其机制研究

Patients with chronic kidney disease (CKD) are at high risk of cardiovascular disease (CVD). Cardic diastolic dysfunction (DD) happens early in the progress of CKD, and is the most common cause of CV mortality in the CKD population, but the mechanism is still less understood. Uremic toxins, among other metabolites, accumulate in patients with chronic kidney disease (CKD), and these are potentially damaging to cardiovascular system. One uremic toxin, p-cresol sulfate (PCS), has been found to associate with DD in our previous clinical multivariate statistical analysis. Further animal experiments also revealed that PCS treatment could promote DD in mice. Profound mechanism studies revealed that PCS has pro-glycation activity, indicate that PCS might have a deleterious impact on diastolic function through advanced glycation end products and their receptor (AGEs-RAGE) pathway. In the future study, we intend to confirm the effects of PCS in mouse model with high PCS level and evaluate RAGE pathway mediation of PCS effects using RAGE-KO mouse. In addition, PCS effects will be assessed in detail in myocytes and cardiac fibroblasts, with mechanism clarification.

慢性肾病（CKD）患者常伴随较高心血管疾病（CVD）发生率，心力衰竭更是CKD患者的主要死因，其中单纯舒张功能不全性心衰的发生更早，但机制不清。尿毒症毒素作为新型CVD危险因子对CKD患者舒张功能不全( DD)发生发展的致病作用值得探讨。本课题组前期临床多因素回归分析发现主要毒素硫酸盐对甲酚（PCS）与CKD患者DD严重程度成正相关；后续动物实验证实单纯PCS干预能促进DD的发生发展，该致病作用与PCS促心肌损伤和纤维化相关；深入机制研究初步证实PCS可显著促进糖化，使损伤心肌表面终末糖化产物（AGE）及其受体（RAGE）含量升高，提示PCS的致病机制可能与AGE-RAGE通路激活相关。后续我们拟以PCS升高为切入点，通过心脏血流动力学分析、体外细胞学实验和在体RAGE基因敲除研究，阐明PCS促心肌损伤及纤维化并最终导致DD的机制，以期为CKD患者心力衰竭的临床治疗提供理论依据和新方向。

慢性肾脏病（CKD）患者常伴有较高的心血管疾病（CVD）发生率，其中心力衰竭（HF）是CKD患者的主要心源性死因。舒张功能不全（DD）发生时间更为提早，是CKD患者HF发生发展的始动环节。尿毒症毒素是因肾功能下降而特意潴留于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。本课题旨在阐明一主要尿毒症毒素硫酸盐对甲酚（PCS）在CKD患者DD发生发展过程中的作用及机制。本课题研究发现终末期肾病患者左室舒张功能与其血浆中PCS浓度水平呈相关性。本课题建立单侧肾切除（UNX）PCS干预小鼠模型，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，并具有促纤维化作用。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炎、促氧化应激机制相关。以上实验数据表明，尿毒症毒素PCS可通过促炎、促氧化应激作用，介导心肌细胞凋亡及纤维化，最终导致左室舒张功能不全。