Zhang Qian, Bai Bing, Ran Lidan, Zhang Wei
Integrative Medicine & Healthy Center, The First People's Hospital of Zunyi, The Third Affiliated Hospital of Zunyi Medical University, 98 Fenghuang Road, Zunyi, 563002, Guizhou, China.
Department of Nephrology, Affiliated Hospital of ZunYi Medical University, 201 Daliang Road, Zunyi, 563003, Guizhou, China.
Sci Rep. 2025 May 3;15(1):15545. doi: 10.1038/s41598-025-96985-6.
Chronic kidney disease (CKD) is highly prevalent, incurable, and lacks effective treatments. Aging is closely linked to various kidney diseases. In this study, we combined CKD and aging using bioinformatics approaches to identify potential anti aging drugs and therapeutic targets for CKD. We analyzed datasets GSE37171 and GSE66494 from the GEO database, identifying 317 differentially expressed genes (DEGs). By intersecting these DEGs with aging related genes, we identified 23 aging associated differential genes (ARDEGs). A protein-protein interaction (PPI) network was constructed using the STRING database, and the top 10 hub ARDEGs were identified using Cytoscape software. Potential anti aging drugs, including Cinnamaldehyde, were identified through the ceRNA and transcription factor regulatory networks, as well as the DGldb database. Among the key regulatory genes identified in CKD patient samples were SOD2, FGF21, FOS, RELA, DDIT4, BMI1, DUSP6, LGALS3, CXCR2, and CEBPB. Cinnamaldehyde and other drugs were found to target aging associated pathways, suggesting their potential to delay CKD progression through modulating these pathways. Finally, we verified the low-expression of DDIT4 and DUSP6, the two targets of Cinnamaldehyde, in unilateral ureteral obstruction (UUO) animal model. Additionally, Cinnamaldehyde was shown to reduce the expression of fibrosis markers such as fibronectin (FN) and α-smooth muscle actin (α-SMA) in HK2 cells under TGF-β1 stimulation. This study provides a foundational understanding of aging related molecular targets in CKD and offers new directions for developing anti aging therapies to treat CKD.
慢性肾脏病（CKD）非常普遍，无法治愈，且缺乏有效的治疗方法。衰老与各种肾脏疾病密切相关。在本研究中，我们使用生物信息学方法将CKD与衰老相结合，以识别潜在的抗衰老药物和CKD的治疗靶点。我们分析了来自基因表达综合数据库（GEO数据库）的数据集GSE37171和GSE66494，鉴定出317个差异表达基因（DEG）。通过将这些DEG与衰老相关基因进行交叉分析，我们鉴定出23个衰老相关差异基因（ARDEG）。使用STRING数据库构建了蛋白质-蛋白质相互作用（PPI）网络，并使用Cytoscape软件鉴定出前10个核心ARDEG。通过ceRNA和转录因子调控网络以及DGldb数据库鉴定出包括肉桂醛在内的潜在抗衰老药物。在CKD患者样本中鉴定出的关键调控基因包括超氧化物歧化酶2（SOD2）、成纤维细胞生长因子21（FGF21）、原癌基因FOS、信号转导和转录激活因子6（RELA）、DNA损伤诱导转录本4（DDIT4）、多梳蛋白抑制复合体1成员BMI1（BMI1）、双特异性磷酸酶6（DUSP6）、半乳糖凝集素3（LGALS3）、趋化因子受体2（CXCR2）和CCAAT增强子结合蛋白β（CEBPB）。发现肉桂醛和其他药物靶向衰老相关途径，表明它们有可能通过调节这些途径来延缓CKD的进展。最后，我们在单侧输尿管梗阻（UUO）动物模型中验证了肉桂醛的两个靶点DDIT4和DUSP6的低表达。此外，在转化生长因子-β1（TGF-β1）刺激下，肉桂醛可降低人近端肾小管上皮细胞（HK2细胞）中纤连蛋白（FN）和α-平滑肌肌动蛋白（α-SMA）等纤维化标志物的表达。本研究为CKD中衰老相关分子靶点提供了基础认识，并为开发抗衰老疗法治疗CKD提供了新方向。
