目的 基于网络药理学与动物实验，探讨糖肾宁对糖尿病肾病（DKD）大鼠结肠与肾脏的保护作用及机制。方法 通过网络药理学筛选糖肾宁活性成分及靶点，构建蛋白质-蛋白质相互作用（PPI）网络，通过基因本体论（GO）与京都基因与基因组百科全书（KEGG）富集分析预测核心信号通路。建立DKD大鼠模型，观察糖肾宁对肾功能及肾组织病理的影响；检测结肠组织Toll样受体4（TLR4）/髓样分化因子88（MyD88）/核因子κB（NF-κB）通路相关蛋白及闭锁小带蛋白1（ZO-1）、闭合蛋白（Occludin）、紧密连接蛋白1（Claudin-1）的表达。结果 网络药理学预测糖肾宁活性成分可能通过多个核心靶点调控多条通路，其中富集于NF-κB通路的靶点包括肿瘤坏死因子（TNF）、前列腺素内过氧化物合酶2（PTGS2）、B细胞淋巴瘤2（BCL2）； IL-17通路的靶点为TNF、白细胞介素6（IL-6）、白细胞介素1β（IL-1β）； HIF-1通路富集的分子为缺氧诱导因子1α（HIF-1α）、蛋白激酶B（AKT1）、BCL2。动物实验证实糖肾宁可改善DKD大鼠肾功能及肾脏病理损伤，抑制结肠TLR4/MyD88/NF-κB通路活化，并上调ZO-1、Occludin、Claudin-1表达。结论 糖肾宁可能通过抑制结肠TLR4/MyD88/NF-κB通路、增强肠道屏障功能，并同步改善肾脏病变，从而改善DKD。

Objective To investigate the protective effects and mechanisms of Tangshenning on the colon and kidneys of rats with diabetic kidney disease (DKD), based on network pharmacology and animal experiments. Methods Active components and targets of Tangshenning were selected using network pharmacology, followed by construction of a protein-protein interaction (PPI) network and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to predict key signaling pathways. A DKD rat model was established to evaluate the effects of Tangshenning on renal function and renal histopathology. In colonic tissue, the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor-κB (NF-κB), as well as the tight junction proteins zonula occludens-1 (ZO-1), Occludin, and Claudin-1, was determined. Results Network pharmacology analysis suggested that the active components of Tangshenning may regulate multiple pathways via several core targets. NF-κB pathway-related targets included tumor necrosis factor (TNF), prostaglandin-endoperoxide synthase 2 (PTGS2), and B-cell lymphoma 2 (BCL2); IL-17 pathway-related targets included interleukin-6 (IL-6), TNF, and interleukin-1β (IL-1β); and HIF-1 pathway-enriched molecules included hypoxia-inducible factor 1α (HIF-1α), protein kinase B (AKT1), and BCL2. Animal experiments showed that Tangshenning improved renal function and ameliorated renal histopathological damage in DKD rats, inhibited activation of the colonic TLR4/MyD88/NF-κB pathway, and upregulated ZO-1, Occludin, and Claudin-1 expression. Conclusion Tangshenning may ameliorate DKD by suppressing the colonic TLR4/MyD88/NF-κB signaling pathway, enhancing intestinal barrier function, and concomitantly improving renal pathology.

R285.5

国家自然科学基金项目（82374268）