title: Urinary proteomic profiling reveals diclofenac-induced renal injury and hepatic regeneration in mice.
abstract: Diclofenac (DF) is a widely used non-steroidal anti-inflammatory drug for the treatment of rheumatic disorders, but is often associated with liver injury. We applied urinary proteomic profiling using MALDI-TOF MS to identify biomarkers for DF-induced hepatotoxicity in mice. Female CH3/HeOUJIco mice were treated with 75mg/kg bw DF by oral gavage and 24h urine was collected. Proteins identified in urine of DF-treated mice included epidermal growth factor, transthyretin, kallikrein, clusterin, fatty acid binding protein 1 and urokinase, which are related to liver regeneration but also to kidney injury. Both organs showed enhanced levels of oxidative stress (TBARS, p<0.01). Kidney injury was confirmed by histology and increased Kim1 and Il-6 mRNA expression levels (p<0.001 and p<0.01). Liver histology and plasma ALT levels in DF-treated mice were not different from control, but mRNA expression of Stat3 (p<0.001) and protein expression of PCNA (p<0.05) were increased, indicating liver regeneration. In conclusion, urinary proteome analysis revealed that DF treatment in mice induced kidney and liver injury. Within 24h, however, the liver was able to recover by activating tissue regeneration processes. Hence, the proteins found in urine of DF-treated mice represent kidney damage rather than hepatic injury.
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
authors.forename: Rachel P L
authors.initials: RP
authors.lastname: van Swelm
authors.forename: Coby M M
authors.initials: CM
authors.lastname: Laarakkers
authors.forename: Jeanne C L M
authors.initials: JC
authors.lastname: Pertijs
authors.forename: Vivienne
authors.initials: V
authors.lastname: Verweij
authors.forename: Rosalinde
authors.initials: R
authors.lastname: Masereeuw
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000652:urine*; D004008:Diclofenac / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000652:urine; D008115:Liver Regeneration / Q000187:drug effects*; D051379:Mice; D020543:Proteome; D011897:Random Allocation; D059467:Transcriptome
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015850:Interleukin-6; D020543:Proteome; D004008:Diclofenac