Local macrophage proliferation in the pathogenesis of glomerular crescent formation in rat anti-glomerular basement membrane (GBM) glomerulonephritis

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Abstract
SUMMARY: Glomerular crescent formation is a feature of aggressive forms of glomerulonephritis. The conventional view of crescent formation within Bowman's space involves proliferation of parietal epithelial cells and the recruitment of blood monocytes. However, the potential role of local macrophage proliferation in this process has not been investigated. The current study examines macrophage proliferation within Bowman's space on the basis of expression of the proliferating cell nuclear antigen (PCNA) in a rat model of crescentic glomerulonephritis (accelerated anti-GBM disease). ED1+ macrophages accounted for 42% of cells within early cellular crescents, and 38% of these crescent macrophages were proliferating on the basis of PCNA expression. Macrophages became the dominant cell population in advanced cellular and fibrocellular crescents (64–71%), and there was a significant increase in the level of macrophage proliferation, with 62% and 67% of ED1+ macrophages expressing the PCNA, respectively. This high level of macrophage proliferation was confirmed by incorporation of bromo-deoxyuridine and the presence of mitotic figures within crescents. Indeed, macrophages accounted for 73% of all proliferating cells within advanced and fibrocellular crescents. Macrophage proliferation within Bowman's space was a local event, as shown by a lack of proliferating monocytes in the circulation, the presence of mitotic figures within crescents and a reciprocal relationship between the numbers of ED1+PCNA+ cells within Bowman's space compared with that in the capillary tuft during the progression from early to advanced and fibrocellular crescents. In conclusion, this study has changed the conventional view of the pathogenesis of crescent formation in glomerulonephritis with the demonstration of substantial local macrophage proliferation within Bowman's space. It is proposed that local proliferation is a major mechanism of macrophage accumulation within crescents and plays an important role in the progression of epithelial-dominated early cellular crescents to macrophage-dominated advanced and fibrocellular cellular crescents.