RAS抑制剂茯苓皮三萜酸利尿及抗肾间质纤维化物质基础及作用机制研究

肾间质纤维化是慢性肾功能衰竭（CRF）主要的特征，如何利用药物干预肾间质纤维化是防治CRF的关键。从中药寻找通过阻断肾素-血管紧张素系统（RAS）的药物治疗CRF是一条重要途径。我们初步研究发现茯苓皮中茯苓酸类化合物能阻断RAS，预实验结果表明茯苓酸类化合物有较强利尿作用，其中茯苓酸A和茯苓新酸通过阻断RAS对5/6肾切除诱导的大鼠发挥治疗作用。本课题拟基于此研究基础，采用生理盐水负荷水潴留大鼠模型和5/6肾切除大鼠模型，借助天然产物化学、药理学和分子生物学技术较深入地研究：1）系统鉴定茯苓酸类利尿化合物，评价其利尿活性；2）茯苓酸类利尿化合物对CRF的防治效果；3）RAS抑制剂茯苓酸类化合物对CRF大鼠肾脏TGF-β/Smad和Wnt/β-catenin信号通路表达的干预作用，阐明其抗肾间质纤维化的机制。本项目的开展将为揭示茯苓皮利尿及抗肾间质纤维化的药效物质基础及作用机制提供科学依据。

Tubulointerstitial fibrosis is the main pathologic feature of chronic renal failure (CRF). How to intervene tubulointerstitial fibrosis by drug is an important path for the treatment of CRF. Our previous studies demonstrated that ethyl acetate extract and tetracyclic triterpenoid compound poricoic acid A and dehydrotrametenolic acid were diuretic bioactive fraction and compounds of Poria cocos epidermis, respectively. The diuretic compound poricoic acid A and dehydrotrametenolic acid can treat 5/6 nephrectomized rats through the inhibition of RAS. Based on our previous studies, this project will employ normal saline-loaded rats and 5/6 nephrectomized rats to clarify several issues. By using the methods of natural product chemistry, pharmacology and molecular biology, the objectives of the current effort are 1) to indentify the diuretic conponents of ethyl acetate extract of Poria cocos epidermis and evaluate their diuretic bioactivity; 2) to explore therapeutic effect of diuretic compounds on the treatment of CRF rats; 3) to explore action mechanism of RAS inhibitors diuretic compounds on the regulation of TGF-β/Smad and Wnt/β-catenin pathways in the kidney tissue of CRF rats to reveal the intervention of diuretic compounds on TGF-β/Smad and Wnt/β-catenin pathways. This study will illuminate effective constituents and action mechanism of Poria cocos epidermis on the treatment of diuresis and anti-tubulointerstitial fibrosis.