NGAL (product of the LCN2 gene) also known as human neutrophil lipocalin, lipocalin-2, siderocalin, or LCN2, neutrophil gelatinase-associated lipocalin, lipocalin 2, and neutrophil lipocalin is a 25-kDa protein initially identified in neutrophil specific granules. NGAL is widely expressed in a variety of human tissues, including, kidney following injury to the renal tubules, trachea, lungs, stomach and large intestines (colon) and its plasma levels can also increase due to hepatic production. Low level expression of NGAL in a variety of epithelia may be increased in inflammation or cancers. NGAL functions in iron homeostasis through binding of siderophores, leading to iron chelation and inhibition of bacterial cell growth or inhibition of apoptosis or oxidative stress in mammalian cells.
With kidney injury, NGAL is upregulated in the thick ascending limb of the loop of Henle, distal tubule and collecting duct, and is secreted into the urine as well as plasma. In mouse models, strongly increased NGAL mRNA and protein in the kidney parenchyma and urine are observed shortly after cisplatin administration or renal ischemia and precede changes in sCr. Plasma levels of NGAL are normally low, and NGAL in the glomerular filtrate is nearly completely reabsorbed by the megalin-cubilin transporter complex in the proximal tubule. With increased urinary protein load (protein overload nephropathy), saturation of the re-absorption capacity of this complex can lead to increased urinary NGAL and tubular back-leak can result in increases in plasma NGAL. In addition, DIKI can cause increased expression and release of NGAL as a protective mechanism as shown for other “tubular stress” proteins such as KIM-1. As a consequence, conditions which lead either to saturation or impairment of the re-absorption complex or to increased de novo expression of NGAL in kidney are expected to demonstrate the utility of NGAL as a kidney biomarker in the context of drug development. Expression of NGAL in the kidney is dramatically increased by ischemic or nephrotoxic kidney injury.
Urinary NGAL is actively being investigated, and in some cases utilized, for the prediction of AKI in a number of clinical settings including interventional trials for AKI, the diagnosis and management of cardiorenal syndrome and in patients undergoing cardiac surgery, in the emergency room, and in the intensive care unit (ICU). Recent reviews, from publications representing several thousand patients, summarize the promising clinical utility of NGAL for the prediction of AKI. sCr and urine output, current diagnostic measures of AKI, do not distinguish between hemodynamic changes due to reduced glomerular filtration rate (GFR) and structural kidney damage. Because NGAL is rapidly upregulated following kidney tissue injury, it is a highly attractive biomarker for the sensitive monitoring of DIKI in clinical trials.
Human NGAL is a low molecular weight 25kDa glycoprotein and a member of the lipocalin superfamily, a single chain monomer that binds and transports small lipophilic/ hydrophobic molecules. NGAL is released by activated neutrophils, can form dimers and small amounts of higher oligomers, and complexes with matrix metalloproteinase 9 (MMP-9, gelatinase B). NGAL can also bind to specific cell surface receptors. NGAL has been identified as an iron-transporting protein during nephrogenesis, demonstrating a role for NGAL in renal organogenesis. It plays important roles in the kidneys, such as induction of the genesis of tubular epithelium. NGAL also is anti-inflammatory and antiapoptotic and as a transport protein is involved in iron-trafficking.
