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

Rahul D. Pawar, Milena Pitashny, Simona Gindea, Arlene Tan Tieng, Benjamin Levine, Beatrice Goilav, Sean R. Campbell, Yumin Xia, Xiaoping Qing, David B. Thomas, Leal Herlitz, Thorsten Berger, Tak W. Mak, Chaim Putterman

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Objective 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. Methods 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. Results 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. Conclusion 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.

Original languageEnglish (US)
Pages (from-to)1620-1631
Number of pages12
JournalArthritis and Rheumatism
Volume64
Issue number5
DOIs
StatePublished - May 2012

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Nephritis
Antibodies
Kidney
Lupus Nephritis
Antinuclear Antibodies
Lipocalin-2
Knockout Mice
Iron-Binding Proteins
Urine
Apoptosis
Passive Immunization
Mesangial Cells
Inbred C57BL Mouse
Proteinuria
Caspase 3

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Neutrophil gelatinase-associated lipocalin is instrumental in the pathogenesis of antibody-mediated nephritis in mice. / Pawar, Rahul D.; Pitashny, Milena; Gindea, Simona; Tieng, Arlene Tan; Levine, Benjamin; Goilav, Beatrice; Campbell, Sean R.; Xia, Yumin; Qing, Xiaoping; Thomas, David B.; Herlitz, Leal; Berger, Thorsten; Mak, Tak W.; Putterman, Chaim.

In: Arthritis and Rheumatism, Vol. 64, No. 5, 05.2012, p. 1620-1631.

Research output: Contribution to journalArticle

Pawar, RD, Pitashny, M, Gindea, S, Tieng, AT, Levine, B, Goilav, B, Campbell, SR, Xia, Y, Qing, X, Thomas, DB, Herlitz, L, Berger, T, Mak, TW & Putterman, C 2012, 'Neutrophil gelatinase-associated lipocalin is instrumental in the pathogenesis of antibody-mediated nephritis in mice', Arthritis and Rheumatism, vol. 64, no. 5, pp. 1620-1631. https://doi.org/10.1002/art.33485
Pawar, Rahul D. ; Pitashny, Milena ; Gindea, Simona ; Tieng, Arlene Tan ; Levine, Benjamin ; Goilav, Beatrice ; Campbell, Sean R. ; Xia, Yumin ; Qing, Xiaoping ; Thomas, David B. ; Herlitz, Leal ; Berger, Thorsten ; Mak, Tak W. ; Putterman, Chaim. / Neutrophil gelatinase-associated lipocalin is instrumental in the pathogenesis of antibody-mediated nephritis in mice. In: Arthritis and Rheumatism. 2012 ; Vol. 64, No. 5. pp. 1620-1631.
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abstract = "Objective 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. Methods 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. Results 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. Conclusion 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.",
author = "Pawar, {Rahul D.} and Milena Pitashny and Simona Gindea and Tieng, {Arlene Tan} and Benjamin Levine and Beatrice Goilav and Campbell, {Sean R.} and Yumin Xia and Xiaoping Qing and Thomas, {David B.} and Leal Herlitz and Thorsten Berger and Mak, {Tak W.} and Chaim Putterman",
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AU - Tieng, Arlene Tan

AU - Levine, Benjamin

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AU - Campbell, Sean R.

AU - Xia, Yumin

AU - Qing, Xiaoping

AU - Thomas, David B.

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AU - Berger, Thorsten

AU - Mak, Tak W.

AU - Putterman, Chaim

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N2 - Objective 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. Methods 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. Results 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. Conclusion 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.

AB - Objective 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. Methods 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. Results 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. Conclusion 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.

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