Comparative analysis of novel noninvasive renal biomarkers and metabonomic changes in a rat model of gentamicin nephrotoxicity.
Although 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 kidney injury molecule (Kim-1), clusterin, lipocalin-2, and tissue inhibitor of metalloproteinase 1 (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 (1)H-NMR and gas chromatography-mass spectrometry (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 (1)H-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 S(1) and S(2) 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, noninvasive biomarkers of nephrotoxicity.
Department of Toxicology, University of Würzburg, 97078 Würzburg, Germany.
Max
M
Sieber
Dana
D
Hoffmann
Melanie
M
Adler
Vishal S
VS
Vaidya
Matthew
M
Clement
Joseph V
JV
Bonventre
Nadine
N
Zidek
Eva
E
Rached
Alexander
A
Amberg
John J
JJ
Callanan
Wolfgang
W
Dekant
Angela
A
Mally
D000704:Analysis of Variance; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000633:toxicity*; D015415:Biomarkers / Q000652:urine*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D051152:Clusterin / Q000235:genetics / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D015870:Gene Expression / Q000187:drug effects; D005839:Gentamicins / Q000008:administration & dosage / Q000633:toxicity*; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism; D008297:Male; D055432:Metabolomics; D009336:Necrosis / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D025341:Principal Component Analysis; D012372:ROC Curve; D051381:Rats; D017208:Rats, Wistar; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism
D000900:Anti-Bacterial Agents; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D051152:Clusterin; D005839:Gentamicins; D054834:Lipocalins; D019715:Tissue Inhibitor of Metalloproteinase-1; C498500:Clu protein, rat; C110936:Havcr1 protein, rat