Evaluation of novel biomarkers of nephrotoxicity in two strains of rat treated with Cisplatin.
Cisplatin is an anticancer agent that induces renal proximal tubule lesions in many species. Studies were conducted in Sprague-Dawley and Han-Wistar rats to evaluate the utility of novel preclinical biomarkers of nephrotoxicity for renal lesions caused by this compound. Groups of 10 males of each strain were given a single intraperitoneal injection of 0.3, 1, or 3 mg/kg cisplatin and were sacrificed on days 2, 3, and 5. The novel biomarkers α-glutathione-S-transferase (α-GST) (for proximal tubular injury), μ-glutathione-S-transferase (μ-GST) (for distal tubular injury), clusterin (for general kidney injury), and renal papillary antigen-1 (RPA-1) (for collecting duct injury) were measured in urine by enzyme immunoassay. Histologically, degeneration and necrosis of the S3 segment of the renal proximal tubule were observed on day 2 (Han-Wistar) and days 3 and 5 (both strains) at 1 and 3 mg/kg. Results showed that in both strains of rats, urinary α-GST and clusterin can be detected in urine soon after injury, are more sensitive than BUN and serum creatinine, and therefore are usable as noninvasive biomarkers of proximal tubule injury. Changes in both μ-GST or RPA-1 were considered to represent secondary minor effects of proximal tubular injury on distal segments of the nephron.
Gautier
Jean-Charles
JC
sanofi-aventis R&D, Paris, France.
Riefke
Björn
B
Walter
Jakob
J
Kurth
Petra
P
Mylecraine
Lou
L
Guilpin
Valérie
V
Barlow
Norman
N
Gury
Thierry
T
Hoffman
David
D
Ennulat
Daniela
D
Schuster
Kerstin
K
Harpur
Ernie
E
Pettit
Syril
S
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism*; D002945:Cisplatin / Q000633:toxicity*; D051152:Clusterin / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000175:diagnosis* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015203:Reproducibility of Results; D013045:Species Specificity; D013047:Specific Pathogen-Free Organisms
D000970:Antineoplastic Agents; D015415:Biomarkers; D051152:Clusterin; D005982:Glutathione Transferase; D002945:Cisplatin