Amelioration of cisplatin-induced acute kidney injury by recombinant neutrophil gelatinase-associated lipocalin

Abstract

We investigated the protective effect and mechanism of neutrophil gelatinase-associated lipocalin (NGAL) in a murine model of cisplatin-induced nephrotoxicity. Male Swiss-Webster mice were assigned to four groups (n = 10 in each group). Control mice received vehicle only. Mice in the experimental group were given a single intraperitoneal injection of cisplatin (20 mg/kg) to induce nephrotoxicity, and were divided into three groups. The first group received 100 μL of saline only via tail vein at the time of cisplatin administration. The second group was given biologically active recombinant NGAL via tail vein (250 μg/100 μL solution). The third group was injected with a 250 μg/100μL solution of inactivated NGAL. After 4 days, we measured serum creatinine and urinary N-acetyl-β-d-glucosaminidase (NAG), and performed histologic studies. Biologically active NGAL significantly blunted the rise in serum creatinine (NGAL plus cisplatin 1.33 ± 0.31 versus cisplatin alone 2.43 ± 0.31 mg/dL, p < .001) as well as the increase in urine NAG (NGAL plus cisplatin 60.7 ± 14.2 versus cisplatin alone 120.5 ± 22.5 units/gm creatinine, p < .005). In addition, NGAL conferred a marked reduction in tubule cell necrosis and apoptosis (NGAL plus cisplatin 6.9 ± 1.2 versus cisplatin alone 15.1 ± 3.4 TUNEL positive nuclei per 100 cells, p < .001). These beneficial effects were completely abolished when heat-inactivated NGAL was administered instead of the biologically active form. Since induction of NGAL in kidney tubules is a known physiologic response to cisplatin, the pharmacologic use of NGAL to prevent cisplatin nephrotoxicity is likely to be safe and effective.