Elucidating the time-dependent changes in the urinary metabolome under doxorubicin-induced nephrotoxicity.

Doxorubicin has been indicated to be cardiotoxic and nephrotoxic, and thus it is often used as a model drug. Possible molecular mechanisms of this toxicity have been proposed, however, the systematic investigation of time-related metabolic trajectories specific to renal toxicity has rarely been reported. The present study was designed to assess time-dependent changes in doxorubicin-induced nephropathy through urinary metabolomics and to reveal the molecular mechanism based on key pathways. Urinary metabolomics revealed that the 14th day was the critical time point for model construction. Pathway analysis results showed that 5 pathways with impact (>0.1), FDR (<0.1) and p value (<0.05) were important. Furthermore, three pathways, including butanoate metabolism, alanine, aspartate and glutamate metabolism and arginine and proline metabolism, were focused on and validated by partial least squares regression analysis (PLS-RA) and molecular docking techniques. Our findings also showed that robust metabolomics combined with PLS-RA and molecular docking techniques is promising for elucidating time-dependent changes due to doxorubicin toxicity and for clarifying mechanisms, and the results provide a research foundation for the construction of a nephropathy model.