Logo of clinexpimmunolLink to Publisher's site
Clin Exp Immunol. Nov 1997; 110(2): 233–240.
PMCID: PMC2265489

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


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.

Keywords: macrophage, proliferation, crescent, fibrosis, glomerulonephritis

Full Text

The Full Text of this article is available as a PDF (4.8M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
1. Magil AB, Wadsworth LD. Monocyte involvement in glomerular crescents: a histochemical and ultrastructural study. Lab Invest. 1982;47:160–6. [PubMed]
2. Hancock WW, Atkins RC. Cellular composition of crescents in human rapidly progressive glomerulonephritis identified using monoclonal antibodies. Am J Nephrol. 1984;3:177–81. [PubMed]
3. Bouche A, Droz D, Adafer E, Noel LH. Relationship between the integrity of Bowman's capsule and the composition of cellular crescents in human crescentic glomerulonephritis. Lab Invest. 1987;56:526–33. [PubMed]
4. Lan HY, Nikolic-Paterson DJ, Atkins RC. Involvement of activated periglomerular leukocytes in the rupture of Bowman's capsule and glomerular crescent progression in experimental glomerulonephritis. Lab Invest. 1992;67:743–51. [PubMed]
5. Van Furth R. Phagocytic cells: development and distribution of mononuclear phagocytes in normal steady state and inflammation. In: Gallin JI, Goldstein IM, Synderman R, editors. Inflammation: basic principles and clinical correlates. New York: Raven Press Ltd; 1988. pp. 281–95.
6. Ken PG, Nikolic-Paterson DJ, Lan HY, Rainone S, Tesch G, Atkins RC. Deoxyspergualin suppresses local macrophage proliferation in renal allograft rejection. Transplantation. 1994;58:596–601. [PubMed]
7. Lan HY, Nikolic-Paterson DJ, Atkins RC. Local macrophage proliferation in experimental Goodpasture's syndrome. Nephrology. 1995;1:151–6.
8. Johnson RJ, Garcia RL, Pritzl P, Alpers CE. Platelets mediate glomerular cell proliferation in immune complex nephritis induced by anti-mesangial cell antibodies in the rat. Am J Pathol. 1990;136:369–74. [PMC free article] [PubMed]
9. Ren K, Brentjens J, Chen Y, Brodkin M, Noble B. Glomerular macrophage proliferation in experimental immune complex nephritis. Clin Immunol Immunopathol. 1991;60:384–98. [PubMed]
10. Goto M, Matsuno K, Yamaguchi Y, Ezaki T, Ogawa M. Proliferation kinetics of macrophage subpopulations in a rat experimental pancreatitis model. Arch Histol Cytol. 1993;56:75–82. [PubMed]
11. Lan HY, Nikolic-Paterson DJ, Mu W, Atkins RC. Local macrophage proliferation in the progression of glomerular and tubulointerstitial injury in rat anti-GBM glomerulonephritis. Kidney Int. 1995;48:753–60. [PubMed]
12. Prelich G, Tan C-K, Kostura M, Mathews MB, So AG, Downey KM, Stillman B. Functional identity of proliferating cell nuclear antigen and a DNA polymerase-δ auxiliary protein. Nature. 1987;326:517–20. [PubMed]
13. Morris GF, Mathews MB. Regulation of proliferating cell nuclear antigen during the cell cycle. J Biol Chem. 1989;264:13856–64. [PubMed]
14. Lan HY, Paterson DJ, Atkins RC. Initiation and evolution of interstitial leukocytic infiltration in experimental glomerulonephritis. Kidney Int. 1991;40:425–33. [PubMed]
15. Dijkstra CD, Dopp EA, Joling P, Kraal G. The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies EDI, ED2 and ED3. Immunology. 1985;54:589–99. [PMC free article] [PubMed]
16. Damoiseaux JG, Dopp EA, Calame W, Qiao D, MacPherson GG, Dijkstra CD. Rat macrophage lysosomal membrane antigen recognized by monoclonal antibody EDI. Immunology. 1994;83:140–7. [PMC free article] [PubMed]
17. Waseem NH, Lane DP. Monoclonal antibody analysis of the proliferating cell nuclear antigen (PCNA) J Cell Science. 1990;96:121–9. [PubMed]
18. Lan HY, Mu W, Nikolic-Paterson DJ, Atkins RC. A novel, simple, reliable and sensitive method of multiple immunoenzymic staining: use of microwave oven heating to block antibody cross-reactivity and retrieve antigens. J Histochem Cytochem. 1995;43:97–102. [PubMed]
19. Cattell V, Jamieson SW. The origin of glomerular crescents in experimental nephrotoxic serum nephritis in the rabbit. Lab Invest. 1978;39:584–90. [PubMed]
20. Magil AB. Histogenesis of glomerular crescents: immunohistochemical demonstration of cytokeratin in crescent cells. Am J Pathol. 1985;120:222–9. [PMC free article] [PubMed]
21. Silva FG, Hoyer JR, Pirani CL. Sequential studies of glomerular crescent formation in rats with antiglomerular basement membrane-induced glomerulonephritis and the role of coagulation factors. Lab Invest. 1984;51:404–15. [PubMed]
22. Striker LMM, Killen PD, Chi E, Striker GE. The composition of glomerulosclerosis. I. Studies in focal sclerosis, crescentic glomerulonephritis, and membranoproliferative glomerulonephritis. Lab Invest. 1984;51:181–92. [PubMed]
23. Song Q, Nikolic-Paterson DJ, Atkins RC, Lan HY. Delayed-type hypersensitivity mediates Bowman's capsule rupture in Tamm-Hors-fall protein-induced tubulointerstitial nephritis in the rat. Nephrology. 1996;2:417–27.
24. Lan HY, Nikolic-Paterson DJ, Mu W, Atkins RC. Local macrophage proliferation in the multinucleated giant cell and granuloma formation in experimental Goodpasture's syndrome. Am J Pathol. 1995;147:1214–20. [PMC free article] [PubMed]
25. Roth P, Stanley ER. The biology of CSF-1 and its receptor. Curr Top Microbiol Immunol. 1992;181:141–67. [PubMed]
26. Bloom RD, Florquin S, Singer GG, Brennan DC, Rubin Kelley V. Colony stimulating factor-1 in the induction of lupus nephritis. Kidney Int. 1993;43:1000–9. [PubMed]
27. Rubin Kelley V, Bloom RD, Yui MA, Martin C, Price D. Pivotal role of colony stimulating factor-1 in lupus nephritis. Kidney Int. 1994;45(Suppl):S83–85. [PubMed]
28. Naito T, Yokoyama H, Moore KJ, Dranoff G, Mulligan RC, Kelley VR. Macrophage growth factors introduced into the kidney initiate renal injury. Mol Med. 1996;2:297–312. [PMC free article] [PubMed]
29. Bemhagen J, Bacher M, Calandra T, Metz CN, Doty S, Donnelly T, Bucala R. An essential role for macrophage migration inhibitory factor (MIF) in the tuberculin delayed-type hypersensitivity reaction. J Exp Med. 1996;183:277–82. [PMC free article] [PubMed]
30. Calandra T, Bemhagen J, Mitchell RA, Bucala R. The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med. 1994;179:1895–902. [PMC free article] [PubMed]
31. Bemhagen J, Calandra T, Mitchell RA, et al. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature. 1993;365:756–9. [PubMed]
32. Lan H Y, Mu W, Yang N, et al. De novo renal expression of macrophage migration inhibitory factor (MIF) during the development of rat crescentic glomerulonephritis. Am J Pathol. 1996;149:1119–27. [PMC free article] [PubMed]

Articles from Clinical and Experimental Immunology are provided here courtesy of British Society for Immunology


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...