基于“肠-肾”途径脾虚湿盛型高尿酸血症病理基础的中药效用机制研究

Chinese herbal medicine has a definite advantage in the treatment of hyperuricemia that is seriously harmed to human health. Based on our previous achievements of National Natural Science Fund, the model, that hyperuricemia quail with spleen deficiency and overabundance dampness, was successfully created, and its pathological changes in the liver synthesis pathway of uric acid was clear. In this study, based on the “intestine-kidney” pathway in metabolism of uric acid, a scientific hypothesis will be put forward, that is, the outbreak of hyperuricemia with spleen deficiency and overabundance dampness is closely related to the disorder of uric acid metabolism in intestine and kidney, because the absorption disorder of purine in intestine maybe lead to produce dampness excessively, and the excretion disorder of uric acid in kidney and intestinal maybe lead to the eliminating dampness insufficiently. The Chinese herbal medicine for spleen dampness can act on the metabolism pathway of intestine and kidney, intervene the absorption of purine and the transporter protein for uric acid,such as CNT2/ABCG2/OAT1/OAT3/URAT1/GLUT9,inhibit the generation of endogenous dampness, and promote the excretion of dampness, to play comprehensive effects of lowering uric acid and improving the state of overabundance dampness. Based on the systematical exploring of model pathology, combining with the methods of biochemistry, immunology, molecular biology, and bioinformatics network, this study will explains the pathway and mechanism of Chinese herbal medicine for spleen dampness in the treatment of hyperuricemia from four levels, which are the whole animal, organ, cell and molecular levels. This study will provide new evidence for the pathological basis of hyperuricemia, and new targets for the evaluation of effectiveness of Chinese herbal medicine for spleen dampness.

高尿酸血症严重危害人类健康，中药治疗优势明确。课题组前期完成的国家自然基金，已成功塑造脾虚湿盛型高尿酸血症鹌鹑模型，并明确该模型肝脏尿酸合成途径的病理变化。本次拟切入肝外尿酸代谢的“肠-肾”途径，提出“脾虚湿盛型高尿酸血症的发生是肠-肾尿酸代谢紊乱的综合效应，其中肠道嘌呤吸收紊乱是湿邪内生基础、肠肾尿酸排泄障碍是湿邪清除异常基础；健脾祛湿类中药作用于肠-肾代谢环节，干预嘌呤吸收与尿酸转运蛋白CNT2/ABCG2/OAT1/OAT3/URAT1/GLUT9，发挥抑制湿邪内生和/或促进湿邪排泄效能，是其降血尿酸、改善湿盛状态作用机制”假说。研究从整体、器官、细胞、分子四个层面，结合生化、免疫学及分子生物学等手段，在系统探讨脾虚湿盛型高尿酸血症病理基础上，阐释健脾祛湿类中药治疗高尿酸血症的途径与机制。不仅为高尿酸血症的中医病机认识提供新依据，更为中药健脾祛湿降尿酸效用评价提供新的靶点与证据。

高尿酸血症是嘌呤代谢紊乱引起的慢性代谢性疾病，近年其发病率呈明显上升，严重威胁人类健康。中药对临床脾虚湿盛型高尿酸血症疗效明确。. 本研究以“肠-肾”尿酸代谢途径为新切入点，采用两种高尿酸血症动物模型（鹌鹑、大鼠）、三种离/在体器官模型（离体肾灌流术、离/在体肠灌流术）及三种细胞模型（鹌鹑原代肾小管上皮细胞、HKC细胞、Caco-2细胞），综合运用生化检测、组织病理学、分子生物学及网络药理学等技术，开展了四部分研究：①脾虚湿盛型高尿酸血症模型“湿邪壅滞”的病理研究；②健脾祛湿方药对证干预脾虚湿盛型高尿酸血症的药理研究；③中药干预高尿酸血症作用靶点的体外验证性研究；④健脾祛湿中药干预脾虚湿盛型高尿酸血症效用特点的综合分析。结果显示：脾虚湿盛型高尿酸血症发病机理与肠-肾尿酸代谢异常密切相关，其中肠道嘌呤过量摄取是“湿邪内生”的病理基础，其机制与肠道嘌呤转运蛋白CNT2表达异常相关；肠道及肾脏尿酸排泄障碍是“湿邪清除”异常的病理基础，其机制与尿酸转运体ABCG2/OAT1/OAT3/URAT1/GLUT9表达异常有关。健脾祛湿类中药通过调控CNT2/ABCG2/OAT1/OAT3/URAT1/GLUT9介导的肠-肾尿酸代谢，以抑制肠道湿邪内生、促进肠-肾湿邪排泄，从而发挥改善高血尿酸“湿邪壅滞”降尿酸的综合效用。根据以上研究结果已发表学术论文30篇（SCI 5 篇），申请专利1项，超额完成任务。. 本研究重要发现：系统阐释了肠道嘌呤吸收紊乱与脾虚湿盛型高尿酸血症“湿邪内生”、肠肾尿酸排泌障碍与脾虚湿盛型高尿酸血症“湿邪淸除”异常的病理联系，明确了健脾祛湿中药作用于“肠-肾”代谢途径，干预嘌呤吸收与尿酸转运的作用靶点和效用机制。. 本项目从“肠-肾”途径明确了高尿酸血症的病理基础以及健脾祛湿中药干预脾虚湿盛型高尿酸血症的作用科学实质，为健脾祛湿中药降尿酸效用的阐释提供新路径与研究平台，为临床中药疗效评价及性效特征研究提供了新思路。本研究在病理与药理学上均具国际领先的学术创新，在高尿酸血症的防治方面具重要临床应用价值。