基于NLRP3炎性体在肥胖相关性肾小球病足细胞损伤中的作用探讨姜黄素的干预机制

Now obesity has been a global epidemic. The incidence of obesity related glomerulopathy (ORG) is also increased rapidly. ORG is now considered as a podocyte disease. The clinical manifestations of ORG are proteinuria and renal insufficiency. Renal pathological feature of ORG is the glomerular hypertrophy, with or without segmental sclerosis. Our team has focused on the study of ORG for at least twelve years. We analyzed and reported the clinicopathological features, and measured and determined normal value range of glomerular diameter in Chinese adults. We created a mouse model of ORG and performed intervention studies on this model. We have published several research papers about ORG in Chinese and international journals. Today the treatment of ORG by using western medicine is still limited. it is necessary to find some useful herb for treatment of ORG from traditional Chinese medicine. Our previous study showed that the main component of turmeric, curcumin, can antagonize the podocyte injury of ORG, but the underlie mechanism is still not clear. Based on our previous work, preliminary experiments data and literature review, we propose the hypothesis that activation of NLRP3 inflammasome may play a crucial role in podocyte injury; curcumin could inhibit the activation of NLRP3 inflammasome, up-regulate cell autophagy and ameliorate podocyte injury. Inhibition of NLRP3 inflammasome by curcumin may be one of possible mechanisms that curcumin antagonizes podocyte injury of ORG. Our study is tightly connected with our previous studies. We intend to verify the above hypothesis through ORG mouse model study in vivo and podocyte experiments in vitro. This research is an original study and no such studies were reported before. If this project can be completed well, the pathogenesis of ORG should be further understanding, which could provide a novel direction for ORG treatment in the future.

随肥胖患者增多，近年肥胖相关性肾小球病（ORG）发病率日益增高。ORG是一种足细胞病，临床表现为蛋白尿及渐进性肾功能损伤，病理表现为肾小球肥大，伴或不伴节段性硬化。申请人团队从2002年起对ORG临床、病理和治疗进行了系列研究，并成功地创建了ORG小鼠模型进行干预试验（详见工作基础）。除减肥外，ORG现缺乏有效治疗手段，因此从祖国医药宝库去寻找治疗药物很有必要。申请人在前一个国自然主任基金项目资助下，进行了姜黄主要成分姜黄素拮抗ORG的初步实验研究，本课题拟对姜黄素作用机制做深入探讨。课题假说为：姜黄素通过抑制肾小球足细胞NLRP3炎性体活化、减少炎症因子释放而增强足细胞自噬，减轻足细胞损伤。研究拟用ORG模型小鼠及瘦素刺激的体外培养的足细胞为研究对象，从整体、器官、分子及蛋白质不同层次对上述假说进行验证。本研究为原创性研究，研究成果将为临床应用姜黄素及含姜黄素中药治疗ORG提供理论基础。

目前肥胖相关性肾小球病（ORG）已被公认为是一种足细胞病，临床表现为蛋白尿及渐进性肾功能损伤，直至终末期肾衰竭。其发病率随肥胖患者的增加而显著升高，但治疗手段有限，致病机制尚不完全清楚。.本项目研究了中药姜黄的主要成分-姜黄素拮抗ORG的作用及相关的机制。通过动物和细胞实验，本研究初步证实：1. ORG时肾小球足细胞NLRP3炎性体活化和炎症因子释放，是足细胞损伤的重要机制；抑制NLRP3可显著改善足细胞损伤。2.NLRP3炎性体的上游受体P2X7R介导炎性体的活化，抑制P2X7R受体也能减轻NLRP3炎性体的活化、炎症因子释放和足细胞损伤。3.ORG时NLRP3炎性体活化的重要诱因是脂质异位沉积，通过抑制脂质摄取的受体CD36，能够减轻肾脏脂质沉积，并使NLRP3炎性体活化减少和足细胞损伤减轻。4.姜黄素能够改善ORG模型小鼠的肾脏病变和足细胞损伤情况，并可显著抑制NLRP3炎性体活化；5.体外实验显示，姜黄素也能减轻瘦素刺激足细胞导致的NLRP3炎性体活化和足细胞损伤。综上所述，姜黄素可有效改善ORG的肾脏病变和足细胞损伤，NLRP3炎性体活化是ORG的重要致病因素，姜黄素可通过抑制NLRP3炎性体的活化而发挥肾脏保护作用。.本研究共发表SCI论著4篇，中国核心期刊论著3篇，并培养了本科医师2名，博士后1名，博士生3名，硕士生2名。本研究证实了中药成分治疗ORG的效果和机制，其成果将为临床应用姜黄素及含姜黄素中药治疗ORG提供理论基础，并可进行很好的临床转化。