Molecular mechanisms and potential targets of lycopene for alleviating renal ischemia-reperfusion injury revealed by network pharmacology and animal experiments

Abstract

ObjectiveRenal IRI is one of the leading causes of AKI. How to effectively mitigate renal IRI is important for the recovery of renal function. The regulatory mechanism of lycopene, a natural antioxidant, in renal IRI is currently unknown. Therefore, we utilized network pharmacology and animal experiments to explore the possible mechanisms and potential targets of lycopene for alleviating renal IRI. MethodsWe obtained lycopene-regulated genes and renal IRI-related genes from the CTD database and GeneCards database, respectively. Subsequently, the two were intersected and the intersecting genes we defined as lycopene-regulated genes in renal IRI. Next, we explored their potential biological functions and mechanisms through enrichment analysis. Meanwhile, we constructed a rat renal IRI model and validated the protective effects of lycopene and related mechanisms. To further explore the Hub genes regulated by lycopene, we constructed a PPI protein interactions network and characterized the Hub genes using Cytoscape software. We also verified the expression of Hub genes using animal experiments and molecular docking techniques. Finally, we constructed TF-Hub gene and miRNA-Hub gene regulatory networks. ResultsWe obtained a total of 255 lycopene-regulated genes and 327 renal IRI-related genes. The enrichment analysis revealed that they were closely related to the regulation of oxidative stress as well as the regulation of inflammatory factors. At the same time, the MAPK signaling pathway was significantly enriched. Next, we found in animal experiments that lycopene significantly alleviated the level of oxidative stress and inflammation during renal IRI, and had a protective effect on kidney damage. Also, we found that this protective effect may be achieved by inhibiting the MAPK signaling pathway. Next, we identified a total of five Hub genes using Cytoscape software: TNF, AKT1, MAPK3, IL6 and CASP3. Both animal experiments and molecular docking techniques demonstrated that lycopene can effectively regulate the expression of Hub genes. Finally, our constructed TF-Hub gene and miRNA-Hub gene regulatory network provide a theoretical basis for further regulation of Hub genes in follow-up. ConclusionsThis study suggests that lycopene is a promising option in mitigating renal IRI. Lycopene may exert protective effects by inhibiting the MAPK signaling pathway.