For answers, we must turn to the kidney itself. Indeed, understanding the early stress response of the kidney to acute injuries has revealed a number of potential biomarkers.14–17 The bench-to-bedside journey of neutrophil gelatinase-associated lipocalin (NGAL), arguably the most promising novel AKI biomarker, is chronicled in see more this review. Human NGAL was originally identified as a 25 kDa protein covalently bound to matrix metalloproteinase-9 (MMP-9) from neutrophils.18 Like other
lipocalins, NGAL forms a barrel-shaped tertiary structure with a hydrophobic calyx that binds small lipophilic molecules.19 The major ligands for NGAL are siderophores, small iron-binding molecules. On the one hand, siderophores are synthesized by bacteria to acquire iron from the surroundings, and NGAL exerts a bacteriostatic effect by depleting siderophores. On the other hand, siderophores produced by eukaryotes participate in NGAL-mediated iron shuttling that is critical to various cellular responses such as proliferation and differentiation.20 Although NGAL is expressed only at very low levels in several human tissues,
it is markedly induced in injured epithelial cells, including the kidney, colon, liver and lung. These Selleck LY294002 findings provide a potential molecular mechanism for the documented role of NGAL in enhancing the epithelial phenotype, both during kidney development and following AKI.18 And finally, NGAL is markedly induced in a number of human cancers, where it often represents a predictor of poor prognosis.21 The
over-expressed NGAL protein binds to MMP-9, thereby preventing MMP-9 degradation and increasing MMP-9 enzyme activity. In turn, MMP-9 activity promotes cancer progression by degrading the basement membranes and extracellular matrix, liberating vascular endothelial growth factor, and thus enabling angiogenesis, invasion and metastasis. Preclinical transcriptome profiling studies identified Ngal (also known as lipocalin 2 or lcn2) Clomifene to be one of the most upregulated genes in the kidney very early after acute injury in animal models.22,23 Downstream proteomic analyses also revealed NGAL to be one of the most highly induced proteins in the kidney after ischaemic or nephrotoxic AKI in animal models.24–26 The serendipitous finding that NGAL protein was easily detected in the urine soon after AKI in animal studies has initiated a number of translational studies to evaluate NGAL as a non-invasive biomarker in human AKI. In a cross-sectional study of adults with established AKI (doubling of serum creatinine) from varying aetiologies, a marked increase in urine and serum NGAL was documented by western blotting when compared with normal controls.26 Urine and serum NGAL levels correlated with serum creatinine, and kidney biopsies in subjects with AKI showed intense accumulation of immunoreactive NGAL in cortical tubules, confirming NGAL as a sensitive index of established AKI in humans.
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