Wang Yanzhe, Liu Yuyuan, Chen Sijia, Li Fengqin, Wu Yue, Xie Xinmiao, Zhang Nan, Zeng Chuchu, Bai Linnan, Dai Mengshi, Zhang Ling, Wang Xiaoxia
Department of Nephrology, Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Nephrology, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China.
Front Pharmacol. 2023 Aug 23;14:1201296. doi: 10.3389/fphar.2023.1201296. eCollection 2023.
(SM) is an effective traditional Chinese medicine for treating DKD, but the exact mechanism is elusive. In this study, we aimed to investigate and confirm the method underlying the action of the active components of SM in the treatment of DKD. Renal tissue transcriptomics and network pharmacology of DKD patients was performed to identify the active components of SM and the disease targets of DKD. Next, the point of convergence among these three groups was studied. Potential candidate genes were identified and analyzed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). The component-target networks were modelled and visualized with Cytoscape. In addition, docking studies were performed to validate our potential target predictions. Lastly, and experiments were performed to understand the role of Dehydromiltirone (DHT), the active component of SM, in the phenotypic switching of mesangial cells. Transcriptomics of DKD patients' renal tissues screened 4,864 differentially expressed genes. Eighty-nine active components of SM and 161 common targets were found. Functional enrichment analysis indicated that 161 genes were enriched in apoptosis, the PI3K-AKT signaling pathway, and the AGE-RAGE signaling pathway in diabetes complications. Molecular docking and molecular dynamic simulations show that DHT can bind to functional PIK3CA pockets, thereby becoming a possible inhibitor of PIK3CA. study demonstrated that DHT reduced the expression of phenotypic switching markers α-SMA, Col-I, and FN in HMCs by downregulating the over-activation of the PI3K-AKT signaling pathway through the inhibition of PIK3CA. Furthermore, the DKD mouse model confirmed that DHT could reduce proteinuria and improve glomerular hypertrophy . DHT was identified as the key active component of SM, and its therapeutic effect on DKD was achieved by inhibiting the phenotypic switching of mesangial cells via the PIK3CA signaling pathway.
（丹参）是治疗糖尿病肾病（DKD）的一种有效中药，但其确切机制尚不清楚。在本研究中，我们旨在研究并确认丹参活性成分治疗DKD的作用机制。对DKD患者进行肾组织转录组学和网络药理学研究，以确定丹参的活性成分和DKD的疾病靶点。接下来，研究这三组之间的交汇点。使用基因本体论（GO）和京都基因与基因组百科全书（KEGG）鉴定和分析潜在的候选基因。用Cytoscape对成分-靶点网络进行建模和可视化。此外，进行对接研究以验证我们的潜在靶点预测。最后，进行实验以了解丹参活性成分脱氢丹参酮（DHT）在系膜细胞表型转换中的作用。DKD患者肾组织的转录组学筛选出4864个差异表达基因。发现了89种丹参活性成分和161个共同靶点。功能富集分析表明，161个基因在糖尿病并发症的细胞凋亡、PI3K-AKT信号通路和AGE-RAGE信号通路中富集。分子对接和分子动力学模拟表明，DHT可以与功能性PIK3CA口袋结合，从而成为PIK3CA的可能抑制剂。研究表明，DHT通过抑制PIK3CA下调PI3K-AKT信号通路的过度激活，从而降低人系膜细胞（HMCs）中表型转换标志物α-SMA、I型胶原（Col-I）和纤连蛋白（FN）的表达。此外，DKD小鼠模型证实，DHT可以降低蛋白尿并改善肾小球肥大。DHT被确定为丹参的关键活性成分，其对DKD的治疗作用是通过PIK3CA信号通路抑制系膜细胞的表型转换来实现的。
