Amelioration of Ischemic Acute Renal Injury by Neutrophil Gelatinase-Associated Lipocalin

Abstract

Abstract. Acute renal failure secondary to ischemic injury remains a common problem, with limited and unsatisfactory therapeutic options. Neutrophil gelatinase-associated lipocalin (NGAL) was recently shown to be one of the maximally induced genes early in the postischemic kidney. In this study, the role of NGAL in ischemic renal injury was explored. Intravenous administration of purified recombinant NGAL in mice resulted in a rapid uptake of the protein predominantly by proximal tubule cells. In an established murine model of renal ischemia-reperfusion injury, intravenous NGAL administered before, during, or after ischemia resulted in marked amelioration of the morphologic and functional consequences, as evidenced by a significant decrease in the histopathologic damage to tubules and in serum creatinine measurements. NGALtreated animals also displayed a reduction in the number of apoptotic tubule cells and an increase in proliferating proximal tubule cells after ischemic injury. The results indicate that NGAL may represent a novel therapeutic intervention in ischemic acute renal failure, based at least in part on its ability to tilt the balance of tubule cell fate toward survival.Acute renal failure (ARF) secondary to ischemic injury remains a common and potentially devastating problem in clinical nephrology, with a persistently high rate of mortality despite significant advances in supportive care (1-4). Pioneering studies over several decades have illuminated the roles of persistent vasoconstriction, tubular obstruction, cellular structural and metabolic alterations, and the inflammatory response in the pathogenesis of ARF (4 -7). Although these studies have paved the way for successful therapeutic approaches in animal models, translational research efforts in humans have yielded disappointing results (2-4). The reasons for this may include the multifaceted response of the kidney to ischemia and a lack of early markers for ARF (4 -8). Recent advances in cellular and molecular biology of ischemic renal injury have revealed that proximal tubule cells undergo a complex temporal sequence of events. These include loss of cell polarity, cell death as a result of apoptosis and necrosis, dedifferentiation and proliferation of viable cells, and reestablishment of the epithelial phenotype (6,7). An improved understanding of the early cell injury and repair mechanisms is critical for innovative and effective therapy. Identification of interventions that may oppose tubule cell death and/or enhance the recovery phase therefore is of considerable interest.Attempts to unravel the molecular basis of the myriad early renal responses have been facilitated by recent advances in functional genomics that have yielded new tools for genomewide analysis of complex biologic processes such as ischemic ARF (8 -11). Using cDNA microarray techniques, we recently identified neutrophil gelatinase-associated lipocalin (NGAL) as one of the most dramatically induced transcripts in the kidney early after ischemic injury (11,12). Although previ...

Exogenous Lipocalin 2 Ameliorates Acute Rejection in a Mouse Model of Renal Transplantation

“…The mechanism of renoprotection in this setting is not clear. As demonstrated for renal IRI, Lcn2 ameliorates morphological and functional damage by reducing apoptosis of tubular epithelial cells and stimulating their proliferation, and this apparently depends on the delivery of sufficient amounts of iron to specific cellular structures 25, 26. In a cell model, Lcn2 has been shown to deliver iron and block apoptosis in its iron‐loaded form, whereas it depletes cellular iron and induces apoptosis in its iron‐lacking form 16.…”

“…Endogenous Lcn2 production is probably induced too late to effectively prevent the damage 25, 26. In addition, it is not clear whether endogenously produced Lcn2 appears in its iron‐loaded form and thus would be able to deliver iron to damaged cells.…”

“…Future studies will have to test the outcome in comparison and in combination with immunosuppression in the long term. Because administration of Lcn2 is effective only at the time of transplantation and the protein is rapidly taken up by the kidneys and secreted in the urine 26, Lcn2 treatment might briefly dampen host immune functions 47, 48 but likely will not compromise the recipient's immune system permanently. The treatment holds great promise because it might eventually replace or at least reduce the requirement for chronic immunosuppression and thus avoid its unfavorable side effects.…”

Plasma neutrophil gelatinase-associated lipocalin predicts acute pyelonephritis in children with urinary tract infections

“…It is considered a specific marker of neutrophil activity and a strong bacteriostatic agent, as it involves the antibacterial iron-depletion strategy of the innate immune system (13,26). NGAL is expressed at low levels in normal organs and increases in injured epithelia, including in the lung, colon, and especially in the kidney (11,27,28). The levels of NGAL are not raised in healthy full-term newborns at birth, but neutrophils from newborns, even premature infants, have been able to rapidly release NGAL upon bacterial or fungal stimulation in vivo (15).…”

“…It has been identified as one of the earliest and potentially one of the most indicative biomarkers of acute kidney injury (AKI) from a diverse array of conditions and can differentiate between prerenal and intrinsic causes (6,7). Urinary NGAL (uNGAL) levels increase in patients with different causes of nephropathies (8,9) and might be a valuable tool in monitoring the treatment response of various renal diseases (10,11).…”