Profiling of rat urinary proteomic patterns associated with drug-induced nephrotoxicity using CE coupled with MS as a potential model for detection of drug-induced adverse effects

Abstract

We have investigated urine obtained from Sprague Dawley rats before and after administration of cis-Platin, aiming at the definition of biomarkers for drug-induced cytotoxicity. Rats were treated with 3 or 6 mg/kg cis-Platin (i.p., single injection) and urine samples were collected before and after drug or saline treatment. Analysis of the low molecular weight proteome (<20 kDa) using capillary-electrophoresis coupled mass spectrometry allowed us to tentatively identify 34 urinary peptides that show significant differences between control and treated animals, and hence may serve as a potential biomarker for cis-Platin-induced nephrotoxicity. These biomarkers were confirmed in a blinded assessment of additional samples. The blinded data also revealed time-dependency of induced changes. Some of the potential biomarkers could be sequenced. This information revealed great similarity between cis-Platin-induced changes and significant changes in the urinary proteome of patients suffering from tubular injury (Fanconi syndrome). Our study strongly suggests that (drug-induced) nephrotoxicity can be detected with high accuracy in laboratory rodents using urinary proteome analysis. The effects observed are very similar to those seen in corresponding human diseases and similar approaches may be very helpful in evaluating drug-induced organ damage in preclinical animal models. This study aiming at the definition of biomarkers for drug-induced cytotoxicity may serve as a proof-of-principle for the use of urinary proteomics in assessment of drug-induced nephrotoxicity.