Preventive effect of sulphated colominic acid on P-selectin-dependent infiltration of macrophages in experimentally induced crescentic glomerulonephritis

Abstract

SUMMARY 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 mediate 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.

Glomerular Expression of CD80 and CD86 Is Required for Leukocyte Accumulation and Injury in Crescentic Glomerulonephritis

“…Both of these adhesion molecules are upregulated in glomeruli of animals with crescentic anti-GBM GN and mediate glomerular infiltration of leukocytes (25,34 -36). Inhibition of P-selectin in anti-GBM GN prevents the development of disease by reducing glomerular T cell and/or macrophage recruitment (25,36), and attenuated renal injury in ICAM-1Ϫ/Ϫ mice is associated with reduced glomerular leukocyte infiltration (34). Previous reports have demonstrated that enhanced T cell influx into inflamed tissue (psoriatic skin lesions) as a result of CD80/86 co-stimulation can be associated with increased endothelial expression of P-selectin and ICAM-1 (37).…”

Inhibition of Cultured Bovine Aortic Smooth Muscle Cell Proliferation by Colominic Acid

“…It has been shown that several biological activities of SCA also require the sulfate group. 2,[6][7][8] Thus, the sulfation appears to be in general essential for exhibition or intensification of the biological activities of polysaccharides. In contrast, the present data showed that the inhibitory effect of CA on vascular smooth muscle cell proliferation is unaffected by the sulfation, suggesting that the polysaccharide chain structure of CA interacts for itself with the cells and the sulfate group does not influence the interaction.…”

“…2) have several biological activities including antiviral activities, [3][4][5] inhibition of the cytotoxic action of bee and snake venom, 6) inhibition of P-selectin-dependent macrophage infiltration in the glomeruli in experimental rat crescentic glomerulonephritis 7) and inhibition of fertilization of mouse gametes. …”

“…Sulfated CA (SCA), prepared by the chemical sulfation of CA, 2) have several biological activities including antiviral activities, [3][4][5] inhibition of the cytotoxic action of bee and snake venom, 6) inhibition of P-selectin-dependent macrophage infiltration in the glomeruli in experimental rat crescentic glomerulonephritis 7) and inhibition of fertilization of mouse gametes. 8) Atherosclerosis is the principal vascular lesion in the pathogenesis of myocardial and cerebral infarction, which is initiated by vascular endothelial cell damage followed by an intimal hyperplasia of vascular smooth muscle cells.…”

The Biological Effects of Depolymerized Sodium Spirulan and Sulfated Colominic Acid on Vascular Cells are Beneficial in Preventing Atherosclerosis

“…1B), originally isolated from Escherichia coli K1. 21) Although little is known about the biological activity of CA, O-sulfated CA (SCA), prepared by chemical sulfation of the CA chain, 22) exhibits several biological activities, including antiviral activities, [23][24][25] inhibition of the cytotoxic action of bee and snake venom, 26) inhibition of Pselectin-dependent macrophage infiltration in the glomeruli in experimental rats with crescentic glomerulonephritis, 27) and inhibition of the fertilization of mouse gametes. 28) However, the effects of CA and SCA on the vascular cell functions as well as the blood coagulation-fibrinolytic system have not been investigated.…”