Wang Pengyu, Lan Qing, Huang Qi, Zhang Ruyi, Zhang Shuo, Yang Leiming, Song Yan, Wang Tong, Ma Guandi, Liu Xiufen, Guo Xiying, Zhang Youzhi, Liu Chao
School of Pharmacy, Hubei Engineering Research Center of Traditional Chinese Medicine of South Hubei Province, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China.
School of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430000, China.
Biology (Basel). 2024 Aug 8;13(8):597. doi: 10.3390/biology13080597.
Diabetic nephropathy (DN) is one of the common complications of diabetes and the main cause of end-stage renal disease (ESRD) in clinical practice. Schisandrin A (Sch A) has multiple pharmacological activities, including inhibiting fibrosis, reducing apoptosis and oxidative stress, and regulating immunity, but its pharmacological mechanism for the treatment of DN is still unclear. In vivo, streptozotocin (STZ) and a high-fat diet were used to induce type 2 diabetic rats, and Sch A was administered for 4 weeks. At the same time, protein-protein interaction (PPI) networks were established to analyze the overlapping genes of DN and Sch A. Subsequently, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were performed to determine the hub pathway. In addition, molecular docking was used to preliminarily verify the affinity of hub proteins and Sch A. Further, H&E staining, Sirius red staining, immunohistochemistry, immunofluorescence, and western blot analysis were used to detect the location and expression of related proteins in DN. This study revealed the multi-target and multi-pathway characteristics of Sch A in the treatment of DN. First, Sch A could effectively improve glucose tolerance, reduce urine microprotein and urine creatinine levels, and alleviate renal pathological damage in DN rats. Second, EGFR was the hub gene screened in overlapping genes (43) of Sch A (100) and DN (2524). Finally, it was revealed that Sch A could inhibit the protein expression levels of EGFR and PTRF and reduced the expression of apoptosis-related proteins, and this effect was related to the modulation of the AKT/GSK-3β signaling pathway. In summary, Sch A has a protective effect in DN rats, EGFR may be a potential therapeutic target, throughout modulating AKT/GSK-3β pathway.
糖尿病肾病（DN）是糖尿病常见并发症之一，也是临床实践中终末期肾病（ESRD）的主要病因。五味子甲素（Sch A）具有多种药理活性，包括抑制纤维化、减少细胞凋亡和氧化应激以及调节免疫，但它治疗DN的药理机制仍不清楚。在体内实验中，使用链脲佐菌素（STZ）和高脂饮食诱导2型糖尿病大鼠，并给予Sch A治疗4周。同时，建立蛋白质-蛋白质相互作用（PPI）网络以分析DN和Sch A的重叠基因。随后，进行京都基因与基因组百科全书（KEGG）和基因本体论（GO）分析以确定核心通路。此外，利用分子对接初步验证核心蛋白与Sch A的亲和力。进一步地，采用苏木精-伊红（H&E）染色、天狼星红染色、免疫组织化学、免疫荧光和蛋白质印迹分析来检测DN中相关蛋白的定位和表达。本研究揭示了Sch A治疗DN的多靶点和多途径特征。首先，Sch A可有效改善糖耐量，降低尿微量蛋白和尿肌酐水平，并减轻DN大鼠的肾脏病理损伤。其次，表皮生长因子受体（EGFR）是在Sch A（100个）和DN（2524个）的重叠基因（43个）中筛选出的核心基因。最后，研究表明Sch A可抑制EGFR和多囊蛋白-1受体（PTRF）的蛋白表达水平，并降低凋亡相关蛋白的表达，且这种作用与AKT/糖原合成酶激酶-3β（GSK-3β）信号通路的调节有关。综上所述，Sch A对DN大鼠具有保护作用，EGFR可能是一个潜在的治疗靶点，其通过调节AKT/GSK-3β通路发挥作用。
