Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest

Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA..
Journal of Clinical Investigation (Impact Factor: 13.22). 04/2005; 115(3):610-21. DOI: 10.1172/JCI23056
Source: PubMed


Neutrophil gelatinase-associated lipocalin (Ngal), also known as siderocalin, forms a complex with iron-binding siderophores (Ngal:siderophore:Fe). This complex converts renal progenitors into epithelial tubules. In this study, we tested the hypothesis that Ngal:siderophore:Fe protects adult kidney epithelial cells or accelerates their recovery from damage. Using a mouse model of severe renal failure, ischemia-reperfusion injury, we show that a single dose of Ngal (10 microg), introduced during the initial phase of the disease, dramatically protects the kidney and mitigates azotemia. Ngal activity depends on delivery of the protein and its siderophore to the proximal tubule. Iron must also be delivered, since blockade of the siderophore with gallium inhibits the rescue from ischemia. The Ngal:siderophore:Fe complex upregulates heme oxygenase-1, a protective enzyme, preserves proximal tubule N-cadherin, and inhibits cell death. Because mouse urine contains an Ngal-dependent siderophore-like activity, endogenous Ngal might also play a protective role. Indeed, Ngal is highly accumulated in the human kidney cortical tubules and in the blood and urine after nephrotoxic and ischemic injury. We reveal what we believe to be a novel pathway of iron traffic that is activated in human and mouse renal diseases, and it provides a unique method for their treatment.

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    • "Human NGAL is the most studied of the three suggested markers for early detection of AKI. In crosssectional study of adults with established AKI from varying etiologies, a marked increase in urine NGAL was documented when compared to normal controls (Mori et al., 2005). uNGAL levels correlated with serum creatinine, and kidney biopsies in patients with AKI showed intense accumulation of immunoreactive NGAL in cortical tubules, confirming NGAL as a sensitive index of established AKI. "
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    ABSTRACT: Neutrophil Gelatinase-Associated Lipocalin (NGAL), Kidney Injury Molecule 1 (KIM-1), and interleukin 18 (IL-18) in urine are sensitive quantitative markers for early diagnosis of acute kidney injury (AKI). The purpose of this study was to demonstrate the role of uNGAL, uKIM-1, and uIL-18 for early assessment of renal function. Measurement of structural markers during the first hour’s afterextracorporeal circulation (ECC) in patients undergoing cardiopulmonary bypass (CPB) allows detection of AKI much earlier than measurement of serum creatinine (48 hours following surgery). Early diagnosis and risk stratification of developing AKI are critical for adequate therapy. Results were presented as ratios to creatinine in urine allowing better comparability and reliability for variations of instant samples were compensated. Results of thereceiver-operator-characteristic curve (ROC) analysis of uNGAL/uCreat, uKIM-1/uCreat, anduIL-18/uCreat 2 – 6 hours post-ECC demonstrated highest area under the receiver operator characteristic curve for uKIM-1/uCreat- 0.85 (95% CI 0.75 – 0.95, p<0.01). uIL-18/uCreat achieved similar results- AUC 0.83 (95% CI 0.72 – 0.94, p<0.01). The diagnostic performance of uNGAL/uCreat showed AUC 0.78 (95% CI 0.71 – 0.85, p<0.01). Using a combination of structural and functional markers demonstrated the highest predictive value for the risk of developing AKI compensating the shortcomings of independent measurements of single markers.
    Merit Research Journal of Medicine and Medical Sciences 06/2015; 3(6):228-232. · 0.68 Impact Factor
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    • "In the setting of acute renal failure, serum and urine NGAL levels are elevated from 7-to 16-fold and from 25-to 100-fold, respectively [8]. Consequently, NGAL has been suggested as a sensitive biomarker of acute kidney injury [5] [6] [8]. However, increased NGAL concentrations have also been reported in chronic kidney disease, which presumably reflects the protracted damage to tubular cells irrespective of the glomerular filtration rate (GFR) [5,9–11]. "
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    ABSTRACT: Background: Due to the lack of nephrotoxic activity, proliferation signal inhibitors (PSI) such as everolimus are recommended for immunosuppression after heart transplantation, but the assessment of renal function in patients receiving PSI has led to conflicting results. We examined renal integrity and function using neutrophil gelatinase-associated lipocalin (NGAL) and conventional markers [plasma creatinine, cystatin C, urine albumin, α1-microglobulin (α1M)] in heart transplant patients, who underwent conversion to everolimus due to allograft vasculopathy, graft rejection episodes, or renal function deterioration, and in patients maintained on calcineurin inhibitors (CNI). Methods: This cross-sectional study included 121 consecutive heart transplant recipients: 44 patients received CNI-free immunosuppressive therapy with everolimus and 77 patients received CNI. Renal parameters were determined in plasma and urine samples using standard enzymatic or immunochemical methods. Results: Heart transplant recipients receiving everolimus therapy had significantly lower NGAL concentrations in plasma [median (95% CI): 128 (97-176)ng/mL vs. 252 (224-283)ng/mL, p<0.001] and urine [median (95% CI): 6.4 (4.5-7.6)ng/g vs. 15.7 (10.2-25.9)ng/g creatinine, p<0.001]. In contrast, no significant differences were observed between everolimus- and CNI-treated groups with regard to creatinine and cystatin C, as well as urine albumin and α1M levels. Significant correlations were noted between plasma NGAL and creatinine (r=0.42, p<0.001), cystatin C (r=0.44, p<0.001), N-terminal brain natriuretic propeptide (r=0.31, p<0.01) and indicators of chronic inflammation [lipoprotein-associated phospholipase A2 (Lp-PLA2), r=0.31, p<0.01] and soluble CD40 ligand (sCD40L, r=0.22, p<0.05), and between urinary NGAL and α1M (r=0.21, p<0.05). Multiple regression analysis indicated that cystatin C and Lp-PLA2 were the best predictors of plasma NGAL. Conclusion: The present study documents reduced plasma and urinary NGAL levels in the absence of differences in conventional renal parameters in patients on CNI-free immunosuppressive therapy with everolimus. These results support favorable effects of everolimus on renal integrity in heart transplant recipients.
    Journal of Cardiology 01/2015; 66(4). DOI:10.1016/j.jjcc.2014.12.010 · 2.78 Impact Factor
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    • "In agreement, NGAL has been shown to be involved in the repair of ischemic renal tubular epithelium [36]. Indeed, treatment with exogenous NGAL ameliorates the kidney injury caused by ischemia-reperfusion [45]. This effect is thought to be mediated, at least in part, by favouring epithelial cell dedifferentiation, proliferation and, thus, repair. "
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    ABSTRACT: Background Hypertension and diabetes are the two leading causes of chronic kidney disease (CKD) eventually leading to end stage renal disease (ESRD) and the need of renal replacement therapy. Mortality among CKD and ESRD patients is high, mostly due to cardiovascular events. New early markers of risk are necessary to better anticipate the course of the disease, to detect the renal affection of additive risk factors, and to appropriately handle patients in a pre-emptive and personalized manner. Methods Renal function and NGAL urinary excretion was monitored in rats with spontaneous (SHR) or L-NAME induced hypertension rendered hyperglycemic (or not as controls). Results Combination of hypertension and hyperglycemia (but not each of these factors independently) causes an increased urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL) in the rat, in the absence of signs of renal damage. Increased NGAL excretion is observed in diabetic animals with two independent models of hypertension. Elevated urinary NGAL results from a specific alteration in its tubular handling, rather than from an increase in its renal expression. In fact, when kidneys of hyperglycaemic-hypertensive rats are perfused in situ with Krebs-dextran solution containing exogenous NGAL, they excrete more NGAL in the urine than hypertensive rats. We also show that albuminuria is not capable of detecting the additive effect posed by the coexistence of these two risk factors. Conclusions Our results suggest that accumulation of hypertension and hyperglycemia induces an incipient and quite specific alteration in the tubular handling of NGAL resulting in its increased urinary excretion.
    PLoS ONE 08/2014; 9(8):e105988. DOI:10.1371/journal.pone.0105988 · 3.23 Impact Factor
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