Distinctive roles of neutrophils and monocytes in anti-thy-1 nephritis.
Anti-Thy-1.1 glomerulonephritis as an experimental model for mesangial proliferative glomerulonephritis was induced in Wistar rats by a single injection of monoclonal IgG2a-anti-Thy-1.1 antibody (ER4G). This transient model is complement-mediated and leads to mesangial-cell (MC) lysis followed by MC proliferation, glomerular microaneurysm formation, glomerular influx of polymorphonuclear leukocytes (PMNs) and macrophages, proteinuria, and hematuria. In this study we investigated the distinctive roles of infiltrating PMNs or monocytes/macrophages by treating rats with an antibody against rat integrin CD11b/CD18 (ED7) or by depletion of monocytes with multilamellar clodronate liposomes, respectively. ED7 administration resulted in reduction of the influx of PMNs in glomeruli during the first 6 days after induction of Thy-1.1 nephritis, whereas treatment with an isotype-matched irrelevant antibody (PEN9) or with phosphate-buffered saline had no effect on macrophage influx. Increased glomerular C3 and C6 deposition on days 1 and 3 was seen in the ED7-treated rats but not seen in the control groups. In addition, the ED7-treated group showed an increased number of aneurysmatic glomeruli and more severe hematuria. Monocyte/macrophage depletion led to a significant reduction of mesangial matrix expansion, although mesangial proliferation, proteinuria, and hematuria remained unaltered. These results, together with the known effects of PMN-derived enzymes on C3 cleavage, suggest that a reduction in the influx of PMNs results in sparing of C3 and consequently of more complement activation in the glomerulus with increased complement-mediated damage. Our data indicate that infiltrating PMNs and monocytes/macrophages play distinctive roles during inflammation in this model of MC glomerulonephritis.
Westerhuis
R
R
Departments of Nephrology, Leiden University Medical Center, University of Leiden, Leiden, The Netherlands.
van Straaten
S C
SC
van Dixhoorn
M G
MG
van Rooijen
N
N
Verhagen
N A
NA
Dijkstra
C D
CD
de Heer
E
E
Daha
M R
MR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002452:Cell Count / Q000187:drug effects; D004002:Clodronic Acid / Q000494:pharmacology; D005260:Female; D006417:Hematuria / Q000209:etiology; D007518:Isoantibodies / Q000276:immunology*; D007678:Kidney Glomerulus / Q000473:pathology; D016177:Macrophage-1 Antigen / Q000276:immunology; D008264:Macrophages / Q000473:pathology; D009000:Monocytes / Q000473:pathology / Q000502:physiology*; D009393:Nephritis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology* / Q000652:urine; D009504:Neutrophils / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D000911:Antibodies, Monoclonal; D007518:Isoantibodies; D016177:Macrophage-1 Antigen; C035678:anti-Thy antibody; D004002:Clodronic Acid