heparitin-sulfate and Nephritis--Interstitial

The chemokine monocyte chemoattractant protein (MCP)-1 has been implicated in the monocyte/macrophage infiltration that occurs during tubulointerstitial nephritis (TIN). We investigated the role of MCP-1 in rats with TIN by administering a neutralizing anti-MCP-1 antibody (Ab). We observed significantly reduced macrophage infiltration and delayed neutrophil clearance in the kidneys of TIN model rats treated with the anti-MCP-1 Ab. To exclude the possibility that an observed immune complex could affect the resolution of apoptotic neutrophils via the Fc receptor, TIN model rats were treated with a peptide-based MCP-1 receptor antagonist (RA). The MCP-1 RA had effects similar to those of the anti-MCP-1 Ab. In addition, MCP-1 did not affect macrophage-mediated phagocytosis of neutrophils in vitro. Deposition of the anti-MCP-1 Ab in rat kidneys resulted from its binding to heparan sulfate-immobilized MCP-1, as demonstrated by the detection of MCP-1 in both pull-down and immunoprecipitation assays. We conclude that induction of chemokines, specifically MCP-1, in TIN corresponds with leukocyte infiltration and that the anti-MCP-1 Ab formed an immune complex with heparan sulfate-immobilized MCP-1 in the kidney. Antagonism of MCP-1 in TIN by Ab or RA may alter the pathological process, most likely through delayed removal of apoptotic neutrophils in the inflammatory loci.

Topics: Animals; Antibodies; Antigen-Antibody Complex; Apoptosis; Chemokine CCL2; Chemokines; Chemokines, CXC; Chemotaxis; Cytokines; Escherichia coli; Fibrosis; Heparitin Sulfate; Intercellular Signaling Peptides and Proteins; Kidney; Macrophages, Peritoneal; Nephritis, Interstitial; Neutrophil Infiltration; Neutrophils; Peptide Fragments; Phagocytosis; Rats; Rats, Inbred BN; Receptors, CCR2; Receptors, Chemokine; Time Factors

The saccharide side chains of heparan sulfate (HS) proteoglycans show enormous complexity. These polysaccharides can interact specifically with cytokines such as basic fibroblast growth factor (bFGF). The understanding of HS expression in glomerulosclerosis and interstitial fibrosis, which is still rudimentary, could provide some insight about the role of bFGF in kidney diseases.. Kidney sections were exposed to exogenous bFGF and then to a monoclonal anti-bFGF antibody. Specificity of the interaction between HS and bFGF was established by monitoring concomitant loss of bFGF during selective removal of HS with heparitinase and competitive inhibition studies. To further characterize regional changes in saccharide sequences, heparitinase-generated unsaturated disaccharides, N-sulfated glucosamine-enriched but O-sulfate-scarce portions characteristics of native HS, and such portions characteristic of Engelbreth-Holm-Swarm tumor HS were studied.. HS was detected in interstitial fibrosis and in advanced glomerulosclerosis, whereas bFGF-binding domains were found only in the fibrosis: The distributional pattern of the N-sulfate-enriched and O-sulfate-scarce portions of native HS was similar to that of bFGF-binding domains. Moreover, a small population of parenchymal cells in advanced tubulointerstitial fibrosis with marked cellular infiltration were especially rich in the bFGF-binding domains.. In fibrotic lesions of the peritubular interstitium, HS shows enrichment of bFGF-binding domains. These regions may play an important role in the fibrogenesis through their interaction with endogenous bFGF.

Topics: Adult; Female; Fibroblast Growth Factor 2; Glomerulosclerosis, Focal Segmental; Heparitin Sulfate; Humans; Immunohistochemistry; Kidney Glomerulus; Male; Middle Aged; Nephritis, Interstitial

Topics: Chondroitin; Chondroitin Sulfates; Glomerulonephritis; Glycosaminoglycans; Heparitin Sulfate; Humans; Kidney Tubules; Nephritis, Interstitial

20 healthy children, 20 children with tubulointerstitial nephritis (TIN) and 20 children with glomerulonephritis in the active state were examined. Polyacrylamide gel electrophoresis of urinary proteins, beta-2-microglobulin excretion and acid glycosaminoglycan electrophoresis were performed. Polyacrylamide-gel electrophoresis showed in all the cases with TIN low molecular weight proteinuria, no bands were observed in healthy children and in all the cases of glomerulonephritis high molecular weight proteinuria. Beta-2-microglobulin determination showed no differences between healthy children and children with glomerulonephritis, but showed high levels in the group of children with TIN. Acid glycosaminoglycan electrophoresis showed in the group of children with healthy children a mean chondroitin-4-sulfate-/heparan sulfate ratio (CS/HS) of 3.8 +/- 0.4. Children with TIN presented a low ratio of 1.5 +/- 0.5. Patients with glomerulonephritis showed a mean ratio of 3.7 +/- 0.3. Our results clearly show that tubular damage can be revealed by a low quotient of chondroitin-4-sulfate to heparan sulfate.

Topics: beta 2-Microglobulin; Child; Chondroitin; Chondroitin Sulfates; Electrophoresis, Polyacrylamide Gel; Glycosaminoglycans; Heparitin Sulfate; Humans; Nephritis, Interstitial