Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Neutrophil Gelatinase Associated Lipocalin (NGAL) and Its Role in the Pathogenesis of Nephritis Induced by Pathogenic Antibodies.
Pawar4, Rahul, Gindea4, Simona, Tieng3, Arlene T., Pitashny4, MIlena, Herlitz5, Leal, Levine2, Benjamin E., Berger6, Thorsten
Albert Einstein College of Med, Bronx, NY
Albert Einstein College of Medicine, Woodmere, NY
Albert Einstein College of Medicine, Bronx, NY
Albert Einstein College of Medicine
Columbia-Presbyterian School of Medicine
The Campbell Family Institute for Breast Cancer Research, Toronto, ON, Canada
Anti-dsDNA antibodies are instrumental in the pathogenesis of lupus nephritis, although the mechanism by which these antibodies contribute to kidney damage has yet to be determined conclusively. We had found that treatment of mesangial cells with pathogenic anti-dsDNA antibodies induced the expression of multiple proinflammatory mediators known to be associated with lupus nephritis. One of the most highly induced genes was NGAL (AKA Lipocalin-2). NGAL is upregulated in response to a variety of inflammatory, ischemic, and other insults to the kidney, and in fact is a sensitive and early urine biomarker in several types of human disease.
To determine whether NGAL is expressed in the context of lupus nephritis, and investigate its role in the pathogenesis of renal injury induced by nephritogenic antibodies.
NGAL expression in serum, urine, and kidneys was analyzed serially in the MRL/lpr mouse lupus model. Nephrotoxic serum nephritis (NTS) was induced by passive transfer of preformed rabbit anti-mouse glomerular antibodies to C57Bl/6 wild type and NGAL deficient mice.
With development of disease, MRL/lpr lupus mice displayed higher kidney NGAL expression than age-matched non-autoimmune mice. In addition, serum NGAL was significantly elevated in old MRL/lpr mice, as compared to young MRL/lpr, old MRL/+ and old BALB/c mice. Importantly, NGAL kidney expression in lupus mice significantly correlated with anti-dsDNA antibody titers and the renal pathology score. Significant elevations of kidney, serum and urine NGAL were observed as well in non-autoimmune mice following passive tranfer of rabbit anti-mouse glomerular antibodies and induction of NTS.
To determine if NGAL upregulation is instrumental in antibody mediated nephritis, we compared the severity of renal damage in C57Bl/6 NGAL knockout and wild type mice following induction of NTS. We found that NGAL deficient mice had significantly attenuated proteinuria, and improved renal histopathology (decreased endocapillarly proliferation and immune deposits) as compared to NGAL sufficient mice.
NGAL deficient mice display less kidney pathology following induction of NTS
Similarly, following NTS induction in non-autoimmune mice, NGAL injection significantly exacerbated nephritis (as assessed by increased proteinuria and more severe renal histopathology) and decreased survival. NGAL induced apoptosis via activation of caspase 3 and promoted the expression of inflammatory genes, in kidney cells in vitro and when injected to mice in vivo.
Nephritogenic antibodies upregulate kidney NGAL, which then appears to be instrumental in the pathogenesis of antibody mediated nephritis via promotion of inflammation and/or apoptosis. We are currently studying whether blocking NGAL may be a novel therapeutic approach for lupus nephritis.
To cite this abstract, please use the following information:
Pawar, Rahul, Gindea, Simona, Tieng, Arlene T., Pitashny, MIlena, Herlitz, Leal, Levine, Benjamin E., et al; Neutrophil Gelatinase Associated Lipocalin (NGAL) and Its Role in the Pathogenesis of Nephritis Induced by Pathogenic Antibodies. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2186