Lipocalin-2 was initially identified in 1989 through the detection of its messenger RNA, named 24p3, in simian virus 40-infected kidney cells of mouse models. It was first isolated in human neutrophil granules, leading to its name, neutrophil gelatinase-associated lipocalin (NGAL) . The protein is a 25-kDa glycoprotein that is protease-resistant due to its complex formation with matrix metalloprotease-9 (MMP-9) in human neutrophils .
NGAL plays a crucial role in the innate immune response by sequestering iron and preventing its use by bacteria, thus limiting their growth . It binds to bacterial siderophores, which are iron-chelating molecules, and also to the mammalian siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA). This binding ensures that excess free iron does not accumulate in the cytoplasm, preventing the formation of reactive oxygen species .
Upon encountering invading bacteria, toll-like receptors on immune cells stimulate the synthesis and secretion of NGAL. Secreted NGAL then limits bacterial growth by sequestering iron-containing siderophores . Additionally, NGAL functions as a growth factor and participates in synaptic plasticity .
NGAL is used as a biomarker for kidney injury due to its protease resistance and low molecular weight, which allows it to be excreted and detected in urine . Injured epithelial cells in the kidney secrete a monomeric form of NGAL, while activated neutrophils secrete a dimeric form. This distinction can potentially improve acute kidney injury (AKI) diagnostics by differentiating NGAL of inflammatory origin from that of renal origin .
In AKI patients, NGAL levels are elevated in both blood and urine within two hours of injury, and plasma NGAL has been shown to be predictive of dialysis need . NGAL is also associated with chronic kidney disease, contrast-induced nephropathy, kidney transplant, and mortality . Monitoring NGAL levels provides a more precise and sensitive marker for diagnosing AKI compared to serum creatinine levels, reducing delayed diagnosis and treatment .
The therapeutic potential of NGAL is being explored in various clinical trials. Its role in iron regulation and immune response makes it a promising candidate for therapeutic interventions in diseases characterized by iron dysregulation and bacterial infections . Additionally, NGAL’s involvement in cell regulation, proliferation, and differentiation highlights its potential in cancer therapy .