Therapeutic effect of sulphated hyaluronic acid, a potential selectin‐blocking agent, on experimental progressive mesangial proliferative glomerulonephritis

Abstract

The initial event in the process of leukocyte infiltration is characterized by leukocyte rolling on the surface of the endothelium, which is mediated by selectins. P- and L-selectin bind to the sulphated sugar chains of their natural ligands, including sulphated glycolipids such as sulphatide. Recently, it has been demonstrated that sulphated glycolipids and sulphated oligosaccharides interfere with selectin binding pathways. This study synthesized sulphated hyaluronic acid (SHA), which is a potential selectin-blocking agent, and examined its therapeutic effect on the experimental progressive mesangial proliferative glomerulonephritis induced by anti-Thy-1 monoclonal antibody (1-22-3 MAb) after unilateral nephrectomy. The selectin-inhibitory effect of SHA in vitro was confirmed. SHA inhibited the binding of P- and L-selectin to sulphatide, which is a glycolipid ligand for P- and L-selectin, at a concentration of 1.5 micro g/ml and 100 micro g/ml. Immunohistochemical examination showed that P-selectin was up-regulated in the glomeruli in the 1-22-3 MAb nephritis model, while the ligands for L-selectin were not detected in the glomerular tufts. A single administration of SHA ameliorated proteinuria and glomerular leukocyte infiltration in 24 h after the injection of anti-Thy-1 MAb. Anti-P-selectin MAb, but not anti-L-selectin MAb, inhibited proteinuria and glomerular leukocyte infiltration. To examine further the therapeutic effect of SHA on chronic glomerulonephritis, SHA was administered daily from day 3 to day 14 in this model. Proteinuria and glomerular leukocyte infiltration were significantly diminished in SHA-treated rats on day 14. These results suggest that SHA ameliorated rat progressive mesangial proliferative glomerulonephritis by inhibiting P-selectin-dependent leukocyte infiltration in glomeruli. Sulphated oligosaccharides may be beneficial for the therapy of mesangial proliferative glomerulonephritis.

Elevated Urinary VCAM-1, P-Selectin, Soluble TNF Receptor-1, and CXC Chemokine Ligand 16 in Multiple Murine Lupus Strains and Human Lupus Nephritis

“…Indeed, VCAM-1 has been suggested as a potential therapeutic target in inflammatory end-organ disease (26,27). Likewise, it has been suggested that glomerular disease may be amenable for therapy by blocking P-selectin (42). Based on our Ab blocking studies in the experimental anti-GBM nephritis model, CXCL16 may turn out to be yet another therapeutic target in nephritis (20).…”

Excreted urinary mediators in an animal model of experimental immune nephritis with potential pathogenic significance

“…These 18 mice were divided into 3 groups of 6 each. On days 1,4,8,12,16, and 20, rat anti-mouse CXCL16 antibody (R&D Systems; catalog no. MAB503), 500 g intraperitoneally (n ϭ 6 mice), or rat IgG2A isotype control (R&D Systems; catalog no.…”

“…Finally, we sought to determine the pathophysiologic relevance of these 4 molecules in immune nephritis. Some information is already available concerning the role of VCAM-1, P-selectin, and TNFRI in renal disease (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), as discussed below. However, much less is known about the role of CXCL16, which is a chemokine expressed on dendritic cells and macrophages.…”

Fucosylated chondroitin sulfate attenuates renal fibrosis in animals submitted to unilateral ureteral obstruction: a P-selectin-mediated event?

“…The effect of other sulfated polysaccharides on inflammation has been attributed to their inhibitory action on P-and L-selectins (27). Sulfated hyaluronic acid inhibits selectin-sulfatide binding and attenuates the infiltration of lymphocytes and macrophages in a model of mesangial proliferative glomerulonephritis (16). Furthermore, the integrity of endothelial heparan sulfate domains is crucial for leukocytes infiltration (28).…”