Preventive effect of sulphated colominic acid on P-selectin-dependent infiltration of macrophages in experimentally induced crescentic glomerulonephritis.
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.
Ogawa
D
D
Department of Medicine III, Okayama University Medical School, Japan.
Shikata
K
K
Matsuda
M
M
Okada
S
S
Wada
J
J
Yamaguchi
S
S
Suzuki
Y
Y
Miyasaka
M
M
Tojo
S
S
Makino
H
H
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
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