Glomerulonephritis (GN) is the inflammation of glomeruli within the kidney and is characterized by haematuria, proteinuria, renal failure and hypertension. Crescentic glomerulonephritis is a rapid, progressive type of glomerulonephritis. Influx and proliferation of mononuclear leukocytes and proliferation of epithelial cells within the glomeruli result in crescent formation. If untreated, deposition of matrix will lead to fibrosis of the kidney and eventual renal failure. The molecular mechanisms responsible for crescent formation remain poorly understood. Several animal models are used in the study of the mechanisms of disease, for example, anti-glomerular basement membrane (GBM) glomerulonephritis or nephrotoxic nephritis (NTN) in rats. In this model, GN is induced by injection of antibodies against the glomerular basement membrane.1
Normal leukocyte extravasation into sites of inflammation requires coordinated and local expression of chemokines and adhesion molecules. Although it might be expected that the same repertoire of adhesion molecules would be implicated in glomerular inflammation as elsewhere, there is evidence to suggest that endothelial cells from different vascular beds respond differently to inflammatory mediators. Fractalkine is a membrane-associated chemokine expressed on endothelial cells, but not on leukocytes, suggesting it is of particular importance for leukocyte recruitment from blood.2 Expression is also induced during inflammation. Fractalkine is membrane bound, thus blurring the traditional distinction between adhesion molecules and chemokines. It can directly mediate leukocyte adhesion to activated endothelium via its receptor CX3CR1. Both T cells and macrophages express CX3CR1.
Fractalkine expression is increased in glomerular endothelium upon induction of anti-GBM GN. Levels of CX3CR1 in the nephritic glomerulus are also elevated concordant with infiltration of inflammatory leukocytes. Leukocytes from nephritic glomeruli show a chemotactic response to fractalkine in vitro, which could be blocked by antibodies to CX3CR1.3 Daily injections of anti-CX3CR1 antibodies into rats with GN attenuated leukocyte infiltration (i.e. both T cells and macrophages) into the glomerulus. Kidney histology also showed anti-CX3CR1 antibody-treated rats had minimal pathological damage in the kidneys, including the near abolition of crescent formation. Renal function was also near normal as measured by proteinuria.4 Another anti-fractalkine strategy for GN involves viral MIP-II. Viral MIP-II is encoded by human herpes virus 8, and has antagonistic activity against CX3CR1. In anti-GBM GN, administration of viral MIP-II inhibits chemotaxis of activated leukocytes isolated from nephritic glomeruli, significantly reduces leukocyte infiltration into glomeruli and attenuates proteinuria.5
Additional chemokines have been shown to contribute to GN. IP-10 and MIG induce mesangial cell proliferation, as well as being chemotactic for infiltrating leukocytes.5 MCP-1 and MIP-1 alpha have also been shown to correlate with crescentic GN.6 However, not all anti-chemokine strategies reduce inflammation and disease manifestations. When GN is induced in CCR1 deficient (-/-) mice, they develop a more severe GN and show neutrophil accumulation comparable to wild type with macrophage and T cell recruitment increased. In addition, CCR1 (-/-) mice have a greater degree of proteinuria and higher frequency of crescent formation.7 Thus, therapeutic targeting of chemokine receptors may exacerbate GN disease.