Application of anti-adhesion molecule therapy for glomerulonephritis -Effects of sulfated oligosaccharides as selectin-blocking agents-

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Background. Selectins are adhesion molecules which mediate leukocyte infiltration into inflammatory tissues. P- and L-selectin bind to sulfated oligosaccharide chains on the ligand molecules. Synthesized sulfated oligosaccharides, including sulfated hyarulonic acid (SHA) and sulfated colominic acid (SCA), inhibit both P- and L-selectin-dependent adhesion pathways in vitro. We evaluated the preventive effects of SHA and SCA on rat mesangial proliferative glomerulonephritis and rat crescentic glomerulonephritis.Methods. Female Wistar rats were injected with anti-Thy-1 antibody after unilateral nephrectomy for a mesangial proliferative glomerulonephritis model. Female WKY rats were injected with nephrotoxic serum for a crescentic glomerulonephritis model. Rats were administered with neutralizing or non-neutralizing monoclonal antibodies to rat P-selectin and L-selectin, SHA, hyarulonic acid, SCA and colominic acid. Localization of P-selectin and macrophages were examined by immunohistochemical methods. Gene expression of PDGF B chain in the glomeruli was quantified using real-time RT-PCR method.Results. Increased expression of P-selectin and macrophage infiltration was prominent in the glomeruli in both two models. Proteinuria, crescent formation and glomerular infiltration of macrophages were significantly reduced by anti-P-selectin mAb, but not by anti-L-SL mAb. SHA and SCA reduced proteinuria, macrophage infiltration and crescent formation in dose dependent manner. Gene expression of PDGF B chain was significantly decreased in SHA and SCA treatment groups. In conclusion, SHA and SCA inhibited glomerular macrophage infiltration by blocking P-selectin-dependent adhesion pathway, and prevented disease progression in rat mesangial proliferative glomerulonephritris and rat crescentic glomerulonephritis. We conclude that sulfated oligosaccharides may be beneficial for the treatment of glomerulonephritis.