The protective mechanism of Dehydromiltirone in diabetic kidney disease is revealed through network pharmacology and experimental validation

Yanzhe Wang; Yuyuan Liu; Sijia Chen; Fengqin Li; Yue Wu; Xinmiao Xie; Nan Zhang; Chuchu Zeng; Linnan Bai; Mengshi Dai; Ling Zhang; Xiaoxia Wang

doi:10.3389/fphar.2023.1201296

The protective mechanism of Dehydromiltirone in diabetic kidney disease is revealed through network pharmacology and experimental validation

Front Pharmacol. 2023 Aug 23:14:1201296. doi: 10.3389/fphar.2023.1201296. eCollection 2023.

Authors

Yanzhe Wang^#¹, Yuyuan Liu^#^{1

2}, Sijia Chen^#¹, Fengqin Li¹, Yue Wu¹, Xinmiao Xie¹, Nan Zhang¹, Chuchu Zeng¹, Linnan Bai³, Mengshi Dai⁴, Ling Zhang⁵, Xiaoxia Wang¹

Affiliations

¹ Department of Nephrology, Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² Department of Nephrology, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China.
³ Department of Nephrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁴ Department of Geriatrics, Huashan Hospital, Fudan University, Shanghai, China.
⁵ Department of Obstetrics and Gynecology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.

^# Contributed equally.

Abstract

Background: Salvia miltiorrhiza (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. Methods: 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, in vitro and in vivo experiments were performed to understand the role of Dehydromiltirone (DHT), the active component of SM, in the phenotypic switching of mesangial cells. Results: 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. In vitro 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 in vivo. Conclusion: 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.

Keywords: Dehydromiltirone; PIK3CA; diabetic kidney disease; molecular docking; network pharmacology.

Grants and funding

This work was supported by the National Natural Science Foundation of China (Grant Nos. 82170745, 82000687, and 82100766) and Shanghai Changning “Quality-Balance” Research Talent Development Fund (Grant Nos. CNYZ06).