Unveiling the mechanisms of nephrotoxicity caused by nephrotoxic compounds using toxicological network analysis.

ABSTRACT

Billions of people worldwide have experienced irreversible kidney injuries, which is mainly attributed to the complexity of drug-induced nephrotoxicity. Consequently, there is an urgent need for uncovering the mechanisms of nephrotoxicity caused by compounds. In the present study, a network-based methodology was applied to explore the mechanisms of nephrotoxicity induced by specific compounds. Initially, a total of 42 nephrotoxic compounds and 60 kinds of syndromes associated with nephrotoxicity were collected from public resources. Afterward, network localization and separation algorithms were used to map the targets of compounds and diseases into the human interactome. By doing so, 199 statistically significant nephrotoxic networks displaying the interaction between compound targets and disease genes were obtained, which played pivotal roles in compounds-induced nephrotoxicity. Subsequently, enrichment analysis pinpointed core Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways that highlight commonalities in nephrotoxicity induced by nephrotoxic compounds. It was found that nephrotoxic compounds primarily induce nephrotoxicity by mediating the advanced glycosylation end products-receptor for advanced glycosylation end products signaling pathway in diabetic complications, human cytomegalovirus infection, lipid and atherosclerosis, Kaposi sarcoma-associated herpesvirus infection, apoptosis, and the phosphatidylinositol 3-kinase-Akt pathways. These results provide valuable insights for preventing drug-induced nephrotoxicity. Furthermore, the approaches we used are also helpful in conducting research on other kinds of toxicities.