Adoptive transfer studies demonstrate that macrophages can induce proteinuria and mesangial cell proliferation

Yohei Ikezumi, Lynette A. Hurst, Takao Masaki, Robert C. Atkins, David J. Nikolic-Paterson

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118 Citations (Scopus)

Abstract

Background. Glomerular macrophage accumulation is a feature of proliferative human and experimental glomerulonephritis. However, our understanding of the role of macrophages in the induction of renal injury is based upon indirect evidence from depletion studies, most of which lack specificity for this cell type. Therefore, an adoptive transfer approach was used to directly assess the potential of macrophages to induce renal injury. Methods. Accelerated anti-glomerular basement membrane (anti-GBM) disease was induced in rats by immunization with sheep IgG (day -5), followed by administration of sheep anti-rat GBM serum (day 0), with animals killed on day 2. To facilitate the adoptive transfer studies, immunized animals were made leukopenic by cyclophosphamide (CyPh) given on day -2. Bone marrow-derived (BM) or NR8383 macrophages were transferred by tail vein injection 24 hours after injection of anti-GBM serum, with animals killed 3 or 24 hours after transfer. Results. Pretreatment with CyPh prevented glomerular leukocyte accumulation and completely inhibited proteinuria, glomerular cell proliferation and hypercellularity in accelerated anti-GBM disease. Adoptive transfer led to significant glomerular accumulation of BM or NR8383 macrophages within 3 hours of injection, and this was still evident 24 hours later. Adoptive transfer of BM or NR8383 macrophages induced proteinuria (63 ± 16 BM vs. 5 ± 2 mg/24 h CyPh control; P < 0.001), glomerular cell proliferation (5.1 ± 1.2 BM vs. 0.5 ± 0.1 PCNA+ cells/gcs CyPh; P < 0.001) and glomerular hypercellularity (51.2 ± 2.0 BM vs. 41.9 ± 0.9 nuclei/gcs CyPh; P < 0.001). The degree of renal injury correlated with the number of transferred glomerular macrophages. Two-color immunostaining demonstrated that most glomerular proliferative cell nuclear antigen+ (PCNA+) proliferating cells were OX-7+ mesangial cells. CyPh treatment did not prevent up-regulation of glomerular intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1) expression or an increase in urinary monocyte chemoattractant protein-1 (MCP-1) excretion. Conclusion. This study provides the first direct evidence that macrophages can induce renal injury in terms of proteinuria and mesangial cell proliferation.

Original languageEnglish
Pages (from-to)83-95
Number of pages13
JournalKidney International
Volume63
Issue number1
DOIs
Publication statusPublished - 01-01-2003

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Mesangial Cells
Adoptive Transfer
Proteinuria
Macrophages
Cell Proliferation
Cyclophosphamide
Bone Marrow
Anti-Glomerular Basement Membrane Disease
Kidney
Vascular Cell Adhesion Molecule-1
Wounds and Injuries
Injections
Sheep
Nuclear Antigens
Glomerular Basement Membrane
Chemokine CCL2
Proliferating Cell Nuclear Antigen
Intercellular Adhesion Molecule-1
Glomerulonephritis
Serum

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Ikezumi, Yohei ; Hurst, Lynette A. ; Masaki, Takao ; Atkins, Robert C. ; Nikolic-Paterson, David J. / Adoptive transfer studies demonstrate that macrophages can induce proteinuria and mesangial cell proliferation. In: Kidney International. 2003 ; Vol. 63, No. 1. pp. 83-95.
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Adoptive transfer studies demonstrate that macrophages can induce proteinuria and mesangial cell proliferation. / Ikezumi, Yohei; Hurst, Lynette A.; Masaki, Takao; Atkins, Robert C.; Nikolic-Paterson, David J.

In: Kidney International, Vol. 63, No. 1, 01.01.2003, p. 83-95.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Adoptive transfer studies demonstrate that macrophages can induce proteinuria and mesangial cell proliferation

AU - Ikezumi, Yohei

AU - Hurst, Lynette A.

AU - Masaki, Takao

AU - Atkins, Robert C.

AU - Nikolic-Paterson, David J.

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N2 - Background. Glomerular macrophage accumulation is a feature of proliferative human and experimental glomerulonephritis. However, our understanding of the role of macrophages in the induction of renal injury is based upon indirect evidence from depletion studies, most of which lack specificity for this cell type. Therefore, an adoptive transfer approach was used to directly assess the potential of macrophages to induce renal injury. Methods. Accelerated anti-glomerular basement membrane (anti-GBM) disease was induced in rats by immunization with sheep IgG (day -5), followed by administration of sheep anti-rat GBM serum (day 0), with animals killed on day 2. To facilitate the adoptive transfer studies, immunized animals were made leukopenic by cyclophosphamide (CyPh) given on day -2. Bone marrow-derived (BM) or NR8383 macrophages were transferred by tail vein injection 24 hours after injection of anti-GBM serum, with animals killed 3 or 24 hours after transfer. Results. Pretreatment with CyPh prevented glomerular leukocyte accumulation and completely inhibited proteinuria, glomerular cell proliferation and hypercellularity in accelerated anti-GBM disease. Adoptive transfer led to significant glomerular accumulation of BM or NR8383 macrophages within 3 hours of injection, and this was still evident 24 hours later. Adoptive transfer of BM or NR8383 macrophages induced proteinuria (63 ± 16 BM vs. 5 ± 2 mg/24 h CyPh control; P < 0.001), glomerular cell proliferation (5.1 ± 1.2 BM vs. 0.5 ± 0.1 PCNA+ cells/gcs CyPh; P < 0.001) and glomerular hypercellularity (51.2 ± 2.0 BM vs. 41.9 ± 0.9 nuclei/gcs CyPh; P < 0.001). The degree of renal injury correlated with the number of transferred glomerular macrophages. Two-color immunostaining demonstrated that most glomerular proliferative cell nuclear antigen+ (PCNA+) proliferating cells were OX-7+ mesangial cells. CyPh treatment did not prevent up-regulation of glomerular intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1) expression or an increase in urinary monocyte chemoattractant protein-1 (MCP-1) excretion. Conclusion. This study provides the first direct evidence that macrophages can induce renal injury in terms of proteinuria and mesangial cell proliferation.

AB - Background. Glomerular macrophage accumulation is a feature of proliferative human and experimental glomerulonephritis. However, our understanding of the role of macrophages in the induction of renal injury is based upon indirect evidence from depletion studies, most of which lack specificity for this cell type. Therefore, an adoptive transfer approach was used to directly assess the potential of macrophages to induce renal injury. Methods. Accelerated anti-glomerular basement membrane (anti-GBM) disease was induced in rats by immunization with sheep IgG (day -5), followed by administration of sheep anti-rat GBM serum (day 0), with animals killed on day 2. To facilitate the adoptive transfer studies, immunized animals were made leukopenic by cyclophosphamide (CyPh) given on day -2. Bone marrow-derived (BM) or NR8383 macrophages were transferred by tail vein injection 24 hours after injection of anti-GBM serum, with animals killed 3 or 24 hours after transfer. Results. Pretreatment with CyPh prevented glomerular leukocyte accumulation and completely inhibited proteinuria, glomerular cell proliferation and hypercellularity in accelerated anti-GBM disease. Adoptive transfer led to significant glomerular accumulation of BM or NR8383 macrophages within 3 hours of injection, and this was still evident 24 hours later. Adoptive transfer of BM or NR8383 macrophages induced proteinuria (63 ± 16 BM vs. 5 ± 2 mg/24 h CyPh control; P < 0.001), glomerular cell proliferation (5.1 ± 1.2 BM vs. 0.5 ± 0.1 PCNA+ cells/gcs CyPh; P < 0.001) and glomerular hypercellularity (51.2 ± 2.0 BM vs. 41.9 ± 0.9 nuclei/gcs CyPh; P < 0.001). The degree of renal injury correlated with the number of transferred glomerular macrophages. Two-color immunostaining demonstrated that most glomerular proliferative cell nuclear antigen+ (PCNA+) proliferating cells were OX-7+ mesangial cells. CyPh treatment did not prevent up-regulation of glomerular intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1) expression or an increase in urinary monocyte chemoattractant protein-1 (MCP-1) excretion. Conclusion. This study provides the first direct evidence that macrophages can induce renal injury in terms of proteinuria and mesangial cell proliferation.

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