New insights into the mechanism of triphenyl phosphate and its metabolite diphenyl phosphate in diabetic kidney disease

Diabetic kidney disease is a significant complication of diabetes mellitus, and exposure to certain chemicals may play a role in its development. Triphenyl phosphate (TPHP) is commonly used in plastics and flame retardants. This study aims to investigate the potential impact of TPHP and its metabolite diphenyl phosphate (DPHP) on diabetic kidney disease using various methods, including network toxicology, molecular docking, and cell experiments like CCK8 assay and real-time-PCR. The research examined the relationship between urinary DPHP levels and kidney function in American adults using data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to March 2020. Additionally, the study explored the targets of action for TPHP and DPHP using network toxicity analysis, conducted protein interaction analysis, and explored the functional aspects of action through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Furthermore, the study identified key proteins involved in the action and conducted experimental verification by treating cells with TPHP and DPHP. Toxicity analysis showed that TPHP could cause dose-dependent toxicity in mouse podocyte clone 5 (MPC5) and mouse mesangial cells (MES13). The study also detected mRNA expression of core targets molecularly docked with TPHP and DPHP using real-time-PCR. The results indicated statistically significant regulation of most core targets by TPHP and DPHP in MPC5, MES13, and human kidney-2 cells.