title: Preventive effect of sulphated colominic acid on P-selectin-dependent infiltration of macrophages in experimentally induced crescentic glomerulonephritis.
abstract: Leucocytes infiltrate into renal tissue and are involved in the pathogenesis of crescentic glomerulonephritis. The initial event in the process of leucocyte infiltration is characterized by selectin-mediated leucocyte rolling on endothelial surface. Role of selectins in pathogenesis of glomerulonephritis has still been controversial. Sulphated glycolipids and sulphated polysaccharides interfere with the binding of P- and L-selectin with carbohydrate ligands on endothelial cells or on leucocytes. Here we evaluated the role of selectins and the preventive effects of sulphated colominic acid (SCA), a synthetic sulphated polysaccharide, on experimental crescentic glomerulonephritis in Wistar-Kyoto (WKY) rats. Crescentic glomerulonephritis was induced by injection of nephrotoxic serum (NTS) in WKY rats. Rats subsequently received intraperitoneal injection of saline, neutralizing or non-neutralizing monoclonal antibody (mAb) to rat P-selectin and L-selectin, SCA (5 or 10mg/kg/day) or nonsulphated colominic acid (CA) (10mg/kg/day) for 2 weeks. Localization of P-, E-selectin, ligands for L-selectin and intraglomerular leucocytes was examined by immunohistochemistry. Gene expression of platelet-derived growth factor (PDGF) B chain in glomeruli was quantified using real-time RT-PCR. P-selectin was highly expressed on glomerular endothelial cells after injection of NTS, whereas E-selectin and L-selectin ligands were not detected. Anti-P-selectin mAb, but not anti-L-selectin mAb, significantly reduced glomerular infiltration of macrophages, crescent formation, and proteinuria. SCA also reduced proteinuria, macrophage infiltration, and crescent formation in a dose-dependent manner. Furthermore, SCA suppressed gene expression of PDGF B chain in glomeruli. Our results indicate that P-selectin partially mediates glomerular infiltration of macrophage in experimental crescentic glomerulonephritis. Moreover, SCA may inhibit intraglomerular infiltration of macrophages by interfering with P-selectin-dependent adhesion pathway, and progression of experimental crescentic glomerulonephritis.
authors.affiliation: Department of Medicine III, Okayama University Medical School, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Ogawa
authors.forename: K
authors.initials: K
authors.lastname: Shikata
authors.forename: M
authors.initials: M
authors.lastname: Matsuda
authors.forename: S
authors.initials: S
authors.lastname: Okada
authors.forename: J
authors.initials: J
authors.lastname: Wada
authors.forename: S
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.forename: M
authors.initials: M
authors.lastname: Miyasaka
authors.forename: S
authors.initials: S
authors.lastname: Tojo
authors.forename: H
authors.initials: H
authors.lastname: Makino
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002634:Chemotaxis, Leukocyte; D004353:Drug Evaluation, Preclinical; D019040:E-Selectin / Q000276:immunology / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005921:Glomerulonephritis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007074:Immunoglobulin G / Q000633:toxicity; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism; D019041:L-Selectin / Q000276:immunology / Q000502:physiology; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D015394:Molecular Structure; D019007:P-Selectin / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011134:Polysaccharides / Q000494:pharmacology / Q000627:therapeutic use*; D011485:Protein Binding / Q000187:drug effects; D011507:Proteinuria / Q000209:etiology / Q000517:prevention & control; D020574:Proto-Oncogene Proteins c-sis / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011921:Rats, Inbred WKY
chemical_list: D000911:Antibodies, Monoclonal; D019040:E-Selectin; D007074:Immunoglobulin G; D019007:P-Selectin; D011134:Polysaccharides; D020574:Proto-Oncogene Proteins c-sis; C463021:sulfated colominic acid; D018799:Intercellular Adhesion Molecule-1; D019041:L-Selectin; C014420:colominic acid