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.