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Neutrophil gelatinase-associated lipocalin is instrumental in the pathogenesis of antibody-mediated nephritis in mice.

ABSTRACT: The mechanism by which anti-DNA antibodies mediate lupus nephritis has yet to be conclusively determined. Previously, we found that treatment of mesangial cells with anti-DNA antibodies induced high expression of neutrophil gelatinase-associated lipocalin (NGAL), an iron-binding protein up-regulated in response to kidney injury. We undertook this study to determine whether NGAL is instrumental in the pathogenesis of nephritis, is induced as part of repair, or is irrelevant to damage/repair pathways.To investigate the role of NGAL in antibody-mediated nephritis, we induced nephrotoxic nephritis by passive antibody transfer to 129/SyJ and C57BL/6 mice. To determine if NGAL up-regulation is instrumental, we compared the severity of renal damage in NGAL wild-type mice and NGAL-knockout mice following induction of nephrotoxic nephritis.We found that kidney NGAL expression, as well as urine NGAL levels, were significantly increased in mice with nephrotoxic nephritis as compared to control-injected mice. Tight correlations were observed between NGAL expression, renal histopathology, and urine NGAL excretion. NGAL-knockout mice had attenuated proteinuria and improved renal histopathology compared to wild-type mice. Similarly, following nephritis induction, NGAL injection significantly exacerbated nephritis and decreased survival. NGAL induced apoptosis via caspase 3 activation and up-regulated inflammatory gene expression in kidney cells in vitro and when injected in vivo.We conclude that kidney binding of pathogenic antibodies stimulates local expression of NGAL, which plays a crucial role in the pathogenesis of nephritis via promotion of inflammation and apoptosis. NGAL blockade may be a novel therapeutic approach for the treatment of nephritis mediated by pathogenic antibodies, including anti-glomerular basement membrane disease and lupus nephritis.

SUBMITTER: Pawar RD

PROVIDER: S-EPMC3325360 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Neutrophil gelatinase-associated lipocalin is instrumental in the pathogenesis of antibody-mediated nephritis in mice.

Pawar Rahul D RD Pitashny Milena M Gindea Simona S Tieng Arlene Tan AT Levine Benjamin B Goilav Beatrice B Campbell Sean R SR Xia Yumin Y Qing Xiaoping X Thomas David B DB Herlitz Leal L Berger Thorsten T Mak Tak W TW Putterman Chaim C

Arthritis and rheumatism 20120501 5

<h4>Objective</h4>The mechanism by which anti-DNA antibodies mediate lupus nephritis has yet to be conclusively determined. Previously, we found that treatment of mesangial cells with anti-DNA antibodies induced high expression of neutrophil gelatinase-associated lipocalin (NGAL), an iron-binding protein up-regulated in response to kidney injury. We undertook this study to determine whether NGAL is instrumental in the pathogenesis of nephritis, is induced as part of repair, or is irrelevant to d ...[more]

PMID: 22083497

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Project description:BackgroundObstructive sleep apnea (OSA) is a well-established risk factor for hypertension and cardiovascular morbidity and mortality. More recently, OSA has been implicated as an independent risk factor for chronic kidney disease. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a well-accepted early biomarker of subclinical kidney tubular injury, preceding an increase in serum creatinine. The goal of this study was to determine if an association exists between OSA and increased urinary NGAL levels.MethodsWe prospectively enrolled adult patients from the sleep clinic of an academic medical center. Each underwent polysomnography and submitted a urine specimen upon enrollment. We measured NGAL and creatinine levels on all urine samples before participants received treatment with continuous positive airway pressure (CPAP), and, in a subset of OSA patients, after CPAP therapy. We compared the urinary NGAL/creatinine ratio between untreated participants with and without OSA, and within a subset of 11 OSA patients also after CPAP therapy.ResultsA total of 49 subjects were enrolled: 16 controls based on an apnea-hypopnea index (events with at least 4% oxygen desaturation; AHI-4%) <5 events/hour (mean AHI-4% = 0.59 +/- 0.60); 33 OSA patients based on an AHI-4% >5 events/hour (mean AHI-4% = 43.3 +/- 28.1). OSA patients had a higher mean body-mass index than the control group (36.58 +/- 11.02 kg/m2 vs. 26.81 +/- 6.55 kg/m2, respectively; p = 0.0005) and were more likely to be treated for hypertension (54.5% vs. 6.25% of group members, respectively; p = 0.0014). The groups were otherwise similar in demographics, and there was no difference in the number of diabetic subjects or in the mean serum creatinine concentration (control = 0.86 +/- 0.15 mg/dl, OSA = 0.87 +/- 0.19 mg/dl; p = 0.7956). We found no difference between the urinary NGAL-to-creatinine ratios among untreated OSA patients versus control subjects (median NGAL/creatinine = 6.34 ng/mg vs. 6.41 ng/mg, respectively; p = 0.4148). Furthermore, CPAP therapy did not affect the urinary NGAL-to-creatinine ratio (p = 0.7758 for two-tailed, paired t-test).ConclusionsIn this prospective case-control study comparing patients with severe, hypoxic OSA to control subjects, all with normal serum creatinine, we found no difference between urinary levels of NGAL. Furthermore, CPAP therapy did not change these levels pre- and post-treatment.

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Neutrophil gelatinase-associated lipocalin is instrumental in the pathogenesis of antibody-mediated nephritis in mice.

Publications

Neutrophil gelatinase-associated lipocalin is instrumental in the pathogenesis of antibody-mediated nephritis in mice.

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