组分配伍四逆汤对甲减肾损伤的保护作用及其作用机制研究

The incidence of hypothyroidism are increased day by day,and it always complixatied by kidney injury.At present,we has not seen the research about the hypothyroidism and hypothyroid induced kidney injury at same time.This project is in the light of Chinese medicine theory ,use the component compatibility of Sini decotion to the animal model which has hypothyroid induced kidney injury.Dectect the renal function and the thyroid hormone,to show the relationship between the thyroid hormone and kidney injury,define the protective range of the component compatibility of Sini decotion.All the proteome of the serum .kidney tissue and urine are studied to obtain the mark protein of the hypothyroid induced kidney injury.It has some significance on clinicl fast and handly diagnosis of hypothyroid induced kidney injury.The cell model are combined to study the signal transduction of the hypothyroid induced kidney injury,to clarify the molecular mechanisms of the component compatibility of Sini decotion to hypothyroid induced kidney injury. This project are carried on the previous national natural science foundation which are finished now,it has solid study foundation.Component compatibility of Sini decotion remove useless subatance and obtain the marrow,it can control the qulity ad reduce the dose.This project carry the study on the hypothyroidism and hypothyroid induced kidney injury at some time ,expand the use of Sini decotion,and provide the thinking of Chinese medicine treatment of hypothyroidism.

甲减发病率日益增多，且易并发肾损伤，目前尚未见同时针对甲减和甲减肾损伤的研究报道。本项目以中医理论为指导，采用组分配伍形式的四逆汤对甲减肾损伤动物模型进行治疗，检测肾功能和甲状腺激素水平，探索甲减肾损伤程度与甲状腺激素水平间的对应关系，界定组分配伍四逆汤减肾损伤保护作用的范围；对各组动物血清、肾脏及尿液的蛋白质组展开研究，获取甲减肾损伤的标志性蛋白，为临床简便快速诊断提供可以借鉴的依据；结合细胞实验，研究组分配伍四逆汤对肾损伤相关信号通路转导的影响，阐明其对甲减肾损伤治疗的分子机制。本项目是在已结题国家自然基金项目基础上继续开展研究，具有坚实的前期工作基础；组分配伍既不失传统复方多成分、多靶点的整合作用特点，又可对组成药味所含成分去粗取精，减少服用剂量且质量可控。本项目同时针对甲减及甲减并发肾损伤进行研究，拓展了经方四逆汤运用的新领域，更为中医治疗甲减及甲减肾损伤之本提供新思路。

本项目采用组分配伍形式的四逆汤对甲状腺功能减退症并发肾脏损害的治疗作用、治疗范围及其相关机制经行研究，探索甲减性肾损伤程度与甲状腺激素水平偏离值之间的对应关系，界定组分配伍四逆汤对其保护作用的范围，对血清、甲状腺、肾脏、尿液蛋白质组学进行研究，获取甲减性肾损伤的标志性蛋白。同时对甲减性肾损伤的常见病理类型-膜性肾病的治疗作用进行研究，观察其对非甲减所致的肾损伤是否有保护作用。研究结果表明，组分配伍四逆汤在升高药物造模6、11、16、20周甲减动物甲状腺激素水平的同时，可降低甲减肾损伤动物的尿素氮、肌酐、胱抑素水平，即组分配伍四逆汤可改善不同时期甲减肾损伤的程度，其作用机制与其治疗原发病密切相关，并且可 降低甲减肾损伤动物肾脏P- p38MAPK、α-SMA、Smad2/3、P-Smad2/3蛋白表达。蛋白质组学研究表明，甲减动物血清、甲状腺、肾脏、尿液中蛋白质谱均有明显改变。组分配伍四逆汤可降低被动型Heymann肾炎（膜性肾病的经典模型）大鼠血清肌酐、尿素氮、白蛋白及甘油三酯、胆固醇含量；降低肾脏组织转化生长因子-β1、纤维黏连蛋白、Ⅳ型胶原水平，作用机制与其抑制p38MAPK和ERK/PLA2信号通路的激活有关。组分配伍四逆汤含药血清对NF-kB信号通路研究表明，可抑制NF-κB ρ65及其磷酸化表达，降低ICAM1及MCP1的表达。研究结果表明组分配伍四逆汤对甲减肾损伤有确切的治疗作用，其治疗作用与其治疗甲减原发病的同时具有对肾损伤的保护作用有关。