肠源性尿毒素IS及其受体AhR是降低慢性肾脏病心血管死亡风险的新靶点，与中医“浊毒伤脉”有相通之处。心肌纤维化是大多数心血管疾病共同病理特征，申请人发现糖尿病肾病（DKD）心肌纤维化与IS/AhR异常升高有关，973课题成果糖肾方具有减轻DKD心肌纤维化作用，且基础与临床数据均表明其能够抑制IS升高和AhR激活。故申请人提出：糖肾方通过抑制IS/AhR发挥治疗DKD心肌纤维化的作用。本项目拟采用DKD心肌纤维化模型，利用稳定性同位素示踪等方法更准确地刻画糖肾方对IS全身周转率和AhR激活的抑制水平；研究IS前体生成、合成、转运排泌、沉积环节，阐明药物抑制IS/AhR的途径和关键分子；利用DKD加载IS体内外模型，明确药物抑制IS/AhR的分子机制和物质基础，系统回答糖肾方通过抑制IS/AhR途径治疗DKD心肌纤维化的作用机制。丰富中医”浊毒伤脉”理论，为糖肾方临床合理应用提供精准依据。

Gut-derived uremic toxin, indoxyl sulfate (IS) and aryl hydrocarbon receptor(AhR) are new targets to reduce the risk of cardiovascular death in chronic kidney disease, which have something in common with "turbid toxin and injured pulse" of traditional Chinese medicine. Myocardial fibrosis is a common pathological feature of most cardiovascular diseases. The applicant found that diabetic kidney disease (DKD) myocardial fibrosis is related to the abnormal increase of IS/AhR. The 973 project achievement Tangshen Formula (TSF) has the effect of reducing DKD myocardial fibrosis, and basic and clinical data show that it inhibits the increase of IS and the activation of AhR. Therefore, we propose the hypothesis is that TSF could treat DKD myocardial fibrosis by inhibiting IS/AhR. This project intends to use DKD myocardial fibrosis model to accurately describe the inhibitory effect of TSF on the systemic turnover rate and AhR activation by stable isotope tracer and other methods; To study the production of IS precursor, synthesis, transport, excretion and deposition, elucidate the key mechanism of TSF inhibiting IS/AhR pathway; The molecular mechanism and material basis of drug inhibition of IS/AhR were determined by using the internal and external model of IS plus carrier. The study will systematically answer the mechanism of TSF in treating DKD myocardial fibrosis by inhibiting IS/AhR pathway, enrich the theory of "turbid toxin injuring pulse" in traditional Chinese medicine, and provide a reliable and accurate research evidence for the clinical application of TSF.