Increased expression of monocyte chemoattractant protein-1 in anti-thymocyte antibody-induced glomerulonephritis

The infiltration of monocytes-macrophages in the glomerulus is one of the hallmarks of glomerulonephritis and may play an important pathogenetic role. Monocyte chemoattractant protein-1 (MCP-1) and colony stimulating factor-1 (CSF-1) are monocyte-specific cytokines with chemoattractant and activating activities for monocytes. MCP-1 and CSF-1 can be generated by several cell types, including glomerular mesangial cells, and can be stimulated by cytokines and immune complexes. To study the expression of CSF-1 and MCP-1 in a model of proliferative glomerulonephritis we used Northern blot analysis and immuno-histochemistry. The glomerular lesion was induced in rats by the i.v. injection of a heterologous anti-thymocyte antiserum (ATS), directed against an antigen which is localized on glomerular mesangial cells. Northern blot analysis revealed comparable amounts of CSF-1 in glomeruli isolated from control untreated rats, and from rats after 30 minutes to three weeks of injection of ATS antibody. In control glomeruli no mRNA levels for MCP-1 were detectable, but increased markedly 30 minutes after the induction of the nephritis, were then reduced at 24 hours and increased again at 5 and 21 days after induction of the disease. The increase in mRNA levels for MCP-1 30 minutes or 24 hours after ATS injection was markedly attenuated if rats were complement depleted by cobra venom injection. These time points following antibody injection were associated with mesangial immune complex formation (30 min), mesangiolysis (24 hr) and proliferative glomerulonephritis (5 and 21 days). By immunohistology the presence of MCP-1 was demonstrated in glomeruli with a predominant mesangial distribution. The mesangial immunofluorescence for MCP-1 followed a pattern similar to that of the mRNA for MCP-1 after induction of the disease process, that is, it increased after 30 minutes, decreased after 24 hours and was increased again at three weeks. Within 30 minutes of the antibody injection an increased infiltration of monocytes-macrophages was observed in the glomeruli, which was maintained up to three weeks of induction of the glomerulonephritis. When the rats were decomplemented with cobra venom factor prior to the i.v. injection of ATS, the expression of MCP-1 in glomeruli remained low and the influx of monocytes/macrophages did not appear. We conclude that MCP-1 is increased early on in glomeruli of rats with immune-mediated mesangial proliferative glomerulonephritis. This increase is mediated by complement activation secondary to the in situ immune complex formation at the glomerular mesangium.(ABSTRACT TRUNCATED AT 400 WORDS)