Neutrophil gelatinase-associated lipocalin: a novel early urinary biomarker for cisplatin nephrotoxicity.
BACKGROUND
Cisplatin is one of the most widely used chemotherapeutic agents, but the risk of nephrotoxicity frequently hinders the use of higher doses to maximize its antineoplastic effects. The lack of early biomarkers has impaired our ability to initiate potential therapeutic or preventive interventions in cisplatin nephrotoxicity in a timely manner. In this study, we have explored the expression and urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL) in a mouse model of cisplatin-induced nephrotoxic injury.


METHODS
Mice were subjected to intraperitoneal injections of 20 mg/kg (high dose) or 5 mg/kg (low dose) cisplatin. The expression of NGAL was measured in the kidney and urine by Western analysis and immunofluorescence, and compared to changes in serum creatinine and urinary N-acetyl-beta-D-glucosaminidase (NAG).


RESULTS
Cisplatin resulted in tubule cell necrosis and apoptosis following the high dose, but not the low dose. By Western analysis, NGAL protein was rapidly induced in the kidney within 3 h of high-dose cisplatin. By immunofluorescence, NGAL was induced predominantly in proximal tubule cells in a punctate cytoplasmic distribution, reminiscent of a secreted protein. NGAL was easily detected in the urine by Western analysis within 3 h of cisplatin administration in a dose- and duration-dependent manner. By comparison, changes in urinary NAG or serum creatinine were not evident until 96 h after cisplatin. Using defined concentrations of purified recombinant NGAL, urinary NGAL excretion following cisplatin administration was quantified to be in the 20-80 ng/ml range.


CONCLUSIONS
The results indicate that NGAL represents an early and quantitative urinary biomarker for cisplatin nephrotoxicity.
Mishra
Jaya
J
Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, USA.
Mori
Kiyoshi
K
Ma
Qing
Q
Kelly
Caitlin
C
Barasch
Jonathan
J
Devarajan
Prasad
P
D000209:Acute-Phase Proteins / Q000652:urine*; D000818:Animals; D015415:Biomarkers / Q000652:urine; D004195:Disease Models, Animal; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000652:urine; D000071068:Lipocalin-2; D054834:Lipocalins; D008297:Male; D051379:Mice; D015513:Oncogene Proteins / Q000652:urine*; D011518:Proto-Oncogene Proteins
D000209:Acute-Phase Proteins; D015415:Biomarkers; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins