title: 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.
authors.affiliation: Department of Medicine III, Okayama University Medical School, Japan. mm8059@kchnet.or.jp
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Matsuda
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shikata
authors.forename: Fujio
authors.initials: F
authors.lastname: Shimizu
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyasaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawachi
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kawashima
authors.forename: Jun
authors.initials: J
authors.lastname: Wada
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shikata
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogawa
authors.forename: Shinichiro J
authors.initials: SJ
authors.lastname: Tojo
authors.forename: Kazuo
authors.initials: K
authors.lastname: Akima
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative / Q000188:drug therapy* / Q000378:metabolism; D006820:Hyaluronic Acid / Q000627:therapeutic use*; D007678:Kidney Glomerulus / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D007958:Leukocyte Count; D019007:P-Selectin / Q000378:metabolism; D011507:Proteinuria / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D019087:Selectins / Q000378:metabolism*; D013431:Sulfates / Q000627:therapeutic use; D013433:Sulfoglycosphingolipids / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D019007:P-Selectin; D019087:Selectins; D013431:Sulfates; D013433:Sulfoglycosphingolipids; D019041:L-Selectin; D006820:Hyaluronic Acid