Exploring potential targets and mechanisms of renal tissue damage caused by N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone (6-PPDQ) through network toxicology and animal experiments: A case of chronic kidney disease

Abstract

6-PPDQ is a new type of environmental contaminant contained in tire rubber. No studies have been reported on the potential targets and mechanisms of action of 6-PPDQ on renal tissue damage. In the present study, we used CKD as an example to explore the potential targets and biological mechanisms of renal injury caused by 6-PPDQ using Network toxicology and animal experiments. A total of 1361 6-PPDQ-related target genes were obtained from the CTD database. 17,296 CKD-related target genes were obtained through the GeneCards database. After intersecting the two, a total of 908 intersecting genes were obtained. Next, we constructed a PPI protein interaction network. Using different algorithms in Cytoscape software and “Logistic regression analysis”, five key target genes were finally identified as NOTCH1, TP53, TNF, IL1B and IL6. We constructed a diagnostic model using five key target genes, and the ROC curves, calibration curves and DCA curves proved that the model has good diagnostic value. Molecular docking demonstrated high affinity between 6-PPDQ and five key target gene proteins. In animal experiments, repeated intraperitoneal injections of 6-PPDQ using different concentration gradients for 28 days revealed that the expression levels of five key target genes in renal tissues increased progressively with the increase of the concentration, and the damage to renal tissues was also aggravated. ssGSEA and animal experiments revealed a key role for activation of the MAPK signaling pathway. Finally, we also identified a significant correlation between five key target genes and the level of infiltration of multiple immune cells. In conclusion, these findings suggest that 6-PPDQ can cause damage to renal tissue and that the level of damage progressively increases with increasing concentration. Among them, NOTCH1, TP53, TNF, IL1B and IL6 may be its potential targets of action. Activation of the MAPK signaling pathway is a potential mechanism of action.