Protective effects of Huang-Lian-Jie-Du Decoction on diabetic nephropathy through regulating AGEs/RAGE/Akt/Nrf2 pathway and metabolic profiling in db/db mice

• Published in: Phytomedicine (Stuttgart) 2022-01, Vol.95, p.153777-153777, Article 153777
• Main Authors: Tang, Dan, He, Wen-Jiao, Zhang, Zhi-Tong, Shi, Jing-Jing, Wang, Xue, Gu, Wen-Ting, Chen, Zhi-Quan, Xu, You-Hua, Chen, Yun-Bo, Wang, Shu-Mei
• Format: Article
• Language: English
• Subjects: AGEs/RAGE/Akt/Nrf2 pathway; Animals; Coptis chinensis; Diabetes Mellitus; Diabetic Nephropathies - drug therapy; Diabetic nephropathy; Drugs, Chinese Herbal - pharmacology; Huang-Lian-Jie-Du Decoction; Metabolomics; Mice; Network Pharmacology; NF-E2-Related Factor 2; Proto-Oncogene Proteins c-akt; Rats
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2021.153777

•Network pharmacology indicated AGEs/RAGE pathway for HLJDD against diabetic nephropathy.•HLJDD possessed beneficial effects on diabetic nephropathy in db/db mice.•HLJDD ameliorated diabetic nephropathy via regulation of AGEs/RAGE/Akt/Nrf2 pathway and metabolic profiling. Diabetic nephropathy (DN) is a severe diabetic complication that is the principal cause of end-stage kidney disease worldwide. Huang-Lian-Jie-Du Decoction (HLJDD) is widely used to treat diabetes clinically. However, the nephroprotective effects and potential mechanism of action of HLJDD against DN have not yet been fully elucidated. This study aimed to investigate the potential roles of HLJDD in DN and elucidate its mechanisms in db/db mice. An integrated strategy of network pharmacology, pharmacodynamics, molecular biology, and metabolomics was used to reveal the mechanisms of HLJDD in the treatment of DN. First, network pharmacology was utilized to predict the possible pathways for DN using the absorbed ingredients of HLJDD in rat plasma in silico. Then, combined with histopathological examination, biochemical evaluation immunohistochemistry/immunofluorescence assay, western blot analysis, and UPLC-Q-Orbitrap HRMS/MS-based metabolomics approach were applied to evaluate the efficacy of HLJDD against DN and its underlying mechanisms in vivo. In silico, network pharmacology indicated that the AGEs/RAGE pathway was the most prominent pathway for HLJDD against DN. In vivo, HLJDD exerted protective effects against DN by ameliorating glycolipid metabolic disorders and kidney injury. Furthermore, we verified that HLJDD protected against DN by regulating the AGEs/RAGE/Akt/Nrf2 pathway for the first time. In addition, 22 potential biomarkers were identified in urine, including phenylalanine metabolism, tryptophan metabolism, glucose metabolism, and sphingolipid metabolism. These findings suggest that HLJDD ameliorates DN by regulating the AGEs/RAGE/Akt/Nrf2 pathway and metabolic profiling. [Display omitted]