Interferon-γ augments acute macrophage-mediated renal injury via a glucocorticoid-sensitive mechanism

Yohei Ikezumi, Robert C. Atkins, David J. Nikolic-Paterson

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Macrophages have been implicated in causing renal injury in both human and experimental kidney disease. The aim of the current study was to determine whether modulating the state of macrophage activation directly affects the capacity of these cells to cause renal injury. This was investigated using an adoptive transfer model in which macrophage activation can be manipulated in vitro, using interferon-γ (IFN-γ) or dexamethasone (Dex), and then macrophage-mediated renal injury determined in vivo. In this model, rats were made leukopenic by administration of cyclophosphamide (CyPh). Two days later (day 0), animals were injected with sheep anti-GBM serum followed by a single injection of rat NR8383 macrophages on day 1 and then killed 3 or 24 h after cell transfer. NR8383 macrophages were incubated IFN-γ and/or Dex before adoptive transfer into animals. Induction of proteinuria and glomerular cell proliferation (PCNA + cells) in this model was dependent on transfer of NR8383 macrophages. Exposure of macrophages to IFN-γ for 18 h (but not 3 h) before transfer caused a twofold increase in the degree of proteinuria and glomerular cell proliferation compared with unstimulated cells (Nil versus IFN-γ; P < 0.001). This was due to an increase in the number of transferred macrophages within the glomerulus and a significant increase in degree of renal injury per transferred glomerular macrophage. IFN-γ increased iNOS and PDGF-B gene expression and upregulated adhesion molecule expression in NR8383 macrophages. In contrast, exposure of NR8383 cells to Dex for 18 h (but not 1 h) abrogated renal injury due to a failure of transferred macrophages to accumulate within the glomerulus. In addition, Dex abrogated renal injury caused by IFN-γ-stimulated macrophages. In conclusion, activation of macrophages by IFN-γ, independent of any effect on other leukocytes or renal cells, can substantially augment macrophage-mediated renal injury. This IFN-γ augmentation of renal injury is sensitive to the action of glucocorticoids, which act directly on macrophages to prevent their recruitment to the inflamed glomerulus. This study provides the first evidence that it is possible to directly modulate macrophage-mediated renal injury.

Original languageEnglish
Pages (from-to)888-898
Number of pages11
JournalJournal of the American Society of Nephrology
Volume14
Issue number4
DOIs
Publication statusPublished - 01-04-2003

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Interferons
Glucocorticoids
Macrophages
Kidney
Wounds and Injuries
Dexamethasone
Macrophage Activation
Adoptive Transfer
Proteinuria
Cell Proliferation
Proliferating Cell Nuclear Antigen
Kidney Diseases
Cyclophosphamide
Sheep
Leukocytes
Gene Expression

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

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abstract = "Macrophages have been implicated in causing renal injury in both human and experimental kidney disease. The aim of the current study was to determine whether modulating the state of macrophage activation directly affects the capacity of these cells to cause renal injury. This was investigated using an adoptive transfer model in which macrophage activation can be manipulated in vitro, using interferon-γ (IFN-γ) or dexamethasone (Dex), and then macrophage-mediated renal injury determined in vivo. In this model, rats were made leukopenic by administration of cyclophosphamide (CyPh). Two days later (day 0), animals were injected with sheep anti-GBM serum followed by a single injection of rat NR8383 macrophages on day 1 and then killed 3 or 24 h after cell transfer. NR8383 macrophages were incubated IFN-γ and/or Dex before adoptive transfer into animals. Induction of proteinuria and glomerular cell proliferation (PCNA + cells) in this model was dependent on transfer of NR8383 macrophages. Exposure of macrophages to IFN-γ for 18 h (but not 3 h) before transfer caused a twofold increase in the degree of proteinuria and glomerular cell proliferation compared with unstimulated cells (Nil versus IFN-γ; P < 0.001). This was due to an increase in the number of transferred macrophages within the glomerulus and a significant increase in degree of renal injury per transferred glomerular macrophage. IFN-γ increased iNOS and PDGF-B gene expression and upregulated adhesion molecule expression in NR8383 macrophages. In contrast, exposure of NR8383 cells to Dex for 18 h (but not 1 h) abrogated renal injury due to a failure of transferred macrophages to accumulate within the glomerulus. In addition, Dex abrogated renal injury caused by IFN-γ-stimulated macrophages. In conclusion, activation of macrophages by IFN-γ, independent of any effect on other leukocytes or renal cells, can substantially augment macrophage-mediated renal injury. This IFN-γ augmentation of renal injury is sensitive to the action of glucocorticoids, which act directly on macrophages to prevent their recruitment to the inflamed glomerulus. This study provides the first evidence that it is possible to directly modulate macrophage-mediated renal injury.",
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Interferon-γ augments acute macrophage-mediated renal injury via a glucocorticoid-sensitive mechanism. / Ikezumi, Yohei; Atkins, Robert C.; Nikolic-Paterson, David J.

In: Journal of the American Society of Nephrology, Vol. 14, No. 4, 01.04.2003, p. 888-898.

Research output: Contribution to journalArticle

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