车前子调控肠道色氨酸代谢介导的AHR/NF-κB/Nrf2信号通路抗肾纤维化的物质基础及机制研究

慢性肾脏病患病率和死亡率急剧增长、且预后差，目前尚无有效的治疗手段。利水渗湿中药车前子具有利尿通淋、渗湿止泻之功效，研究表明车前子具有潜在的抗肾纤维化作用，但其物质基础及作用机理尚不明确。本项目前期对车前子中乙酸乙酯部位（EAE）成分进行活性追踪，发现其成分通过拮抗芳烃受体（AHR）/氧化应激信号通路，调节肠道菌群来源的色氨酸代谢和肠道菌群紊乱发挥抗肾纤维化活性。本项目拟采用色谱分离与活性追踪的方法系统鉴定EAE中拮抗AHR信号通路的成分，通过体内外药效学评价，确定目标活性成分，并阐明其抗肾纤维化作用及分子作用机制，明确车前子EAE中成分抗肾纤维化药效物质基础，验证“车前子EAE中化学物质通过调控肠道色氨酸代谢介导的AHR/NF-κB/Nrf2信号通路发挥抗肾纤维化作用”科学假说。本研究拟阐明车前子抗肾纤维化的药效物质及分子作用机制，为防治肾纤维化新药开发奠定基础。

The morbidity and mortality of chronic kidney disease are increased dramatically, and the prognosis is poor. There is so far no effective therapeutic method. The Plantaginis Semen, a traditional Chinese medicine with diuresis and dampness, has the improvement effects on diuresis, gonorrhea, dampness and diarrhea. Studies have shown that Plantaginis Semen has potential effect against renal fibrosis, but its material basis and action mechanism are not yet clear. Our previous study investigated the bioactive compounds of ethyl acetate extraction (EAE) of Plantaginis Semen by using bioactivity-directed method. It was demonstrated that the compounds retarded renal fibrosis through antagonizing aromatic hydrocarbon receptor (AHR)/oxidative stress signaling pathway and regulating gut microbiota-derived tryptophan metabolism and the dysbiosis of gut microbiota. This project intends to use chromatographical separation and bioactivity-directed methods to systematically identify EAE compounds that antagonize AHR signaling pathway, assess their pharmacological activities through in vivo and in vitro method, and clarify their inhibitory effects on renal fibrosis and their molecular mechanism, reveal the material basis of anti-renal fibrosis of the compounds from the EAE of Plantaginis Semen. Our study will verify the scientific hypothesis “the EAE compounds from Plantaginis Semen against renal fibrosis through regulating the AHR/NF-κB/Nrf2 signaling pathway mediated by tryptophan metabolites derived from gut microbiota”. This study will expound the bioactive components and molecular mechanism of Plantaginis Semen against renal fibrosis that will provide the research basis for the research and development of new drugs to prevent and treat renal fibrosis.