ToxSci Advance Access published online on April 6, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp070
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Comparative analysis of novel non-invasive renal biomarkers and metabonomic changes in a rat model of gentamicin nephrotoxicity
* Department of Toxicology, University of Würzburg, 97078 Würzburg, Germany
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Sanofi-Aventis, Drug Safety Evaluation, Hattersheim, Germany
School of Agriculture, Food Science & Veterinary Medicine and Conway Institute of Molecular & Biomedical Research, University College Dublin, Dublin 4, Ireland
Corresponding author: PD Dr. Angela Mally, Department of Toxicology, University of Würzburg, Versbacher Str. 9, 97078 Würzburg, Germany, Tel.: +49-931-20148894, Fax: +49-931-20148865, e-mail: mally{at}toxi.uni-wuerzburg.de
Received January 22, 2009; revision received March 12, 2009; accepted March 27, 2009
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Abstract |
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While early detection of toxicant induced kidney injury during drug development and chemical safety testing is still limited by the lack of sensitive and reliable biomarkers of nephrotoxicity, omics technologies have brought enormous opportunities for improved detection of toxicity and biomarker discovery. Thus, transcription profiling has led to the identification of several candidate kidney biomarkers such as Kim-1, clusterin, lipocalin-2 and Timp-1, and metabonomic analysis of urine is increasingly used to indicate biochemical perturbations due to renal toxicity. This study was designed to assess the value of a combined 1H-NMR and GC-MS metabonomics approach and a set of novel urinary protein markers for early detection of nephrotoxicity following treatment of male Wistar rats with gentamicin (60 and 120 mg/kg bw, s.c.) for 7 days. Time- and dose-dependent separation of gentamicin-treated animals from controls was observed by principal component analysis of 1H-NMR and GC-MS data. The major metabolic alterations responsible for group separation were linked to the gut microflora, thus related to the pharmacology of the drug, and increased glucose in urine of gentamicin treated animals, consistent with damage to the S1 and S2 proximal tubules, the primary sites for glucose reabsorption. Altered excretion of urinary protein biomarkers Kim-1 and lipocalin-2, but not Timp-1 and clusterin, was detected before marked changes in clinical chemistry parameters were evident. The early increase in urine, which correlated with enhanced gene and protein expression at the site of injury, provides further support for lipocalin-2 and Kim-1 as sensitive, non-invasive biomarkers of nephrotoxicity.
Key Words: kidney; nephrotoxicity; biomarker; metabonomics; Kim-1; lipocalin-2.
1 both authors have contributed equally