Identification of Neutrophil Gelatinase-Associated Lipocalin as a Novel Early Urinary Biomarker for Ischemic Renal Injury

Abstract

Abstract. Acute renal failure (ARF) secondary to ischemic injury remains a common and potentially devastating problem. A transcriptome-wide interrogation strategy was used to identify renal genes that are induced very early after renal ischemia, whose protein products might serve as novel biomarkers for ARF. Seven genes that are upregulated Ͼ10-fold were identified, one of which (Cyr61) has recently been reported to be induced after renal ischemia. Unexpectedly, the induction of the other six transcripts was novel to the ARF field. In this study, one of these previously unrecognized genes was further characterized, namely neutrophil gelatinase-associated lipocalin (NGAL), because it is a small secreted polypeptide that is protease resistant and consequently might be readily detected in the urine. The marked upregulation of NGAL mRNA and protein levels in the early postischemic mouse kidney was confirmed. NGAL protein expression was detected predominantly in proliferating cell nuclear antigen-positive proximal tubule cells, in a punctate cytoplasmic distribution that colocalized with markers of late endosomes. NGAL was easily detected in the urine in the very first urine output after ischemia in both mouse and rat models of ARF. The appearance of NGAL in the urine was related to the dose and duration of renal ischemia and preceded the appearance of other urinary markers such as N-acetyl-␤-D-glucosaminidase and ␤2-microglobulin. The origin of NGAL from tubule cells was confirmed in cultured human proximal tubule cells subjected to in vitro ischemic injury, where NGAL mRNA was rapidly induced in the cells and NGAL protein was readily detectable in the culture medium within 1 h of mild ATP depletion. NGAL was also easily detectable in the urine of mice with cisplatininduced nephrotoxicity, again preceding the appearance of N-acetyl-␤-D-glucosaminidase and ␤2-microglobulin. The results indicate that NGAL may represent an early, sensitive, noninvasive urinary biomarker for ischemic and nephrotoxic renal injury.

Early markers of obesity-related renal injury in childhood

“…Neutrophil gelatinase-associated lipocalin Neutrophil gelatinase-associated lipocalin (NGAL), a 25-kDa protein, is known to be released from injured renal tubular cells in acute kidney injury (AKI) before a decrease in the GFR can be detected [14]. In patients with moderate kidney disease, serum and urine NGAL concentrations have been identified to be independent predictors of CKD progression [15].…”

Evaluation of Renal Function Using the Level of Neutrophil Gelatinase-Associated Lipocalin is Not Predictive of Nephrotoxicity Associated with Cisplatin-Based Chemotherapy

“…Neutrophil gelatinase-associated lipocalin (NGAL), a polypeptide bonded with matrix metalloproteinase (MMP) in neutrophils (Kjeldsen et al, 1994), is a promising indicator in acute renal failure (Mishra et al, 2003). NGAL is secreted from the thick-ascending limb of Henle's loop and collecting tubules into the urine.…”

Clinical review: Sepsis and septic shock - the potential of gene arrays

“…Ideally, the RNA source should be relatively homogenous and closely represent the disease/condition biology of interest. For example, the discovery of neutrophil gelatinase-associated lipocalin as a biomarker for acute kidney injury included microarray-based analysis of kidneys from rodents subjected to renal ischemia [7]. Most of the studies described below have used the blood compartment as the RNA source.…”