Caitlin Kelly

Acute renal failure secondary to ischemic injury remains a common problem, with limited and unsatisfactory therapeutic options. Neutrophil gelatinase-associated lipocalin (NGAL) was recently shown to be one of the maximally induced genes early in the postischemic kidney. In this study, the role of NGAL in ischemic renal injury was explored. Intravenous administration of purified recombinant NGAL in mice resulted in a rapid uptake of the protein predominantly by proximal tubule cells. In an established murine model of renal ischemia-reperfusion injury, intravenous NGAL administered before, during, or after ischemia resulted in marked amelioration of the morphologic and functional consequences, as evidenced by a significant decrease in the histopathologic damage to tubules and in serum creatinine measurements. NGAL-treated animals also displayed a reduction in the number of apoptotic tubule cells and an increase in proliferating proximal tubule cells after ischemic injury. The results indicate that NGAL may represent a novel therapeutic intervention in ischemic acute renal failure, based at least in part on its ability to tilt the balance of tubule cell fate toward survival.

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. CONCLUSION: The results indicate that NGAL represents an early and quantitative urinary biomarker for cisplatin nephrotoxicity.