Longitudinal Multi-Omics Characterization of Propyl Gallate-Mediated Nephrotoxicity in Beagles

To increase the oral bioavailability of therapeutic peptides, an enteric coated tablet containing permeation enhancers was developed. Early studies showed signs of nephrotoxicity in dogs administered with tablets formulated with propyl gallate (PG). To characterize the mechanisms of PG-mediated nephrotoxicity, we performed longitudinal multi-omic plasma profiling including proteome and lipidome. Time-series analysis revealed hundreds of lipids and proteins altered because of PG treatment. Multiple lipids belonging to various classes including glycerolipids, glycerophospholipids, sphingomyelins and cholesterol esters were affected by PG. Most dysregulated lipids contained arachidonic acid, a precursor in the biosynthesis of pro-inflammatory lipids, which may reflect damages associated with PG administration. Alteration in the proteome was observed with proteins associated with renal injury, including lipoproteins, proteolysis regulation and proteasome core complex proteins. Altogether, longitudinal multi-omics profiling and integrative analysis provided mechanistic hypotheses of PG-induced nephrotoxicity demonstrating the value of such approach to investigate mechanisms relevant to drug safety.