基于TGF-β/Smad通路和脂质代谢探讨大黄抗肾纤维化的药效物质基础及作用机制

Chronic renal failure (CRF) has an important impact on public health problem worldwide. Renal interstitial fibrosis is the main pathologic feature of CRF. How to intervene progressive renal interstitial fibrosis by drug treatment is very important to the CRF prevention. Traditional Chinese medicine possesses various unique advantages in CRF treatment. As a common traditional Chinese medicine, rhubarb has been used for treating CRF. According to our previous results, the ethyl acetate extract of rhubarb is proven to have a good therapeutic effect on CRF and shows a beneficial effect against renal interstitial fibrosis induced by adenine. However, how the ethyl acetate extract of rhubarb exerts the effect against renal interstitial fibrosis is unknown. Based on our previous experimental results, the objective of the current effort was to study the anti-fbrotic activity of rhubarb; uncover the intervention effect of rhubarb on TGF-β/Smad signaling pathway and illuminate the improvement of rhubarb for lipid metabolisms by using pharmacodynamics, molecular biology and lipidomics. This study will elucidate the intervention effects of ethyl acetate extract of rhubarb on TGF-β/Smad signaling pathway and endogenous lipid biomarkers. This study will provide important insights into the material basis of effective components and action mechanisms of rhubarb against renal interstitial fibrosis.

慢性肾功能衰竭（CRF）已成为影响全球人类健康的重大疾病之一。肾间质纤维化是CRF的重要病理特征之一。如何利用药物干预肾间质纤维化的发展是防治CRF的关键。中药在治疗CRF方面具有众多独特优势，大黄作为临床常用中药已对CRF显示较好的治疗作用。我们前期的研究发现大黄乙酸乙酯提取物对腺嘌呤导致的CRF具有较好的防治作用，能够改善腺嘌呤引起的肾间质纤维化。但是，大黄乙酸乙酯提取物如何抗肾间质纤维化仍不明确。基于我们的研究基础，本课题拟采用药效学、分子生物学及脂质组学方法，首先探讨大黄乙酸乙酯提取物抗肾间质纤维化作用；其次阐明大黄对TGF-β/Smad纤维化信号通路的影响；最后研究CRF脂质代谢状态及大黄对CRF脂质代谢紊乱的干预程度，揭示大黄如何干预TGF-β/Smad信号通路与脂质生物标示物的代谢。本课题的完成将阐明大黄抗肾间质纤维化的药效物质基础，为大黄的作用机制研究提供一定的参考。

慢性肾功能衰竭（CRF）的发病率、死亡率呈上升趋势，已成为影响全球人类健康的重大疾病之一。目前临床尚无有效控制CRF进展的药物，因此寻找治疗CRF的新靶点和新药物具有重要意义。中药在治疗CRF方面具有众多独特优势，大黄作为临床常用中药已对CRF显示较好的治疗作用。本项目通过药效学、分子生物学、代谢组学及脂质组学方法，证明了大黄乙酸乙酯提取物抗肾间质纤维化作用；其次阐明了大黄乙酸乙酯提取物通过干预慢性肾功能衰竭大鼠肾组织中异常的TGF-β/Smad信号通路而抗肾纤维化的分子生物学作用机制；通过脂质组学、生物信息学等方法，鉴定了脂肪酸、溶血卵磷脂、甘油磷脂等脂质代谢产物是慢性肾功能衰竭大鼠血清和肾组织中脂质类生物标示物，揭示了大黄乙酸乙酯提取物通过调控这些异常的脂质代谢产物而抗肾纤维化的生物化学作用机制，为揭示大黄抗肾质纤维化的药效物质基础及作用机制提供一定的参考依据。本课题的完成初步阐明了大黄抗肾间质纤维化的药效物质基础，为大黄的作用机制研究提供一定的参考。