AT(1)-RECEPTOR ANTAGONISTS ABOLISH GLOMERULAR MCP-1 EXPRESSION IN A MODEL OF MESANGIAL PROLIFERATIVE GLOMERULONEPHRITIS

Background: Glomerular accumulation of macrophages/monocytes (M/M) is a typical early feature in the course of anti-thymocyte serum (ATS)-in duced nephritis. We have previously shown that glomerular synthesis an d expression of monocyte-chemoattractant protein-1 (MCP-I) occurs befo re influx of M/M and a neutralizing anti-MCP-l antibody reduced this c ell infiltrate by one third, The present study was undertaken to test the effect of two angiotensin II type 1 (AT(1)) receptor antagonists, losartan and irbesartan, on ATS-stimulated MCP-1 expression as well as glomerular influx of M/M. Methods: Treatment of rats with either losa rtan or irbesartan was started 24 h before administration of ATS. Afte r 24 h, MCP-1 mRNA expression was evaluated by RT-PCR and Northern blo ts. MCP-1 protein was determined by Western blots and chemotactic fact ors released from isolated glomeruli were measured by chemotactic assa y. Kidney sections were stained for rabbit IgG, complement C3, and M/M (ED1 antigen). Results: Both AT(1)-receptor antagonists caused a sign ificant, but not total reduction in MCP-1 mRNA and protein expression 24h after injection of ATS, Treatment with losartan or irbesartan also reduced the chemotactic activity of isolated glomeruli from nephritic animals, Quantification of ED 1-positive cells revealed that losartan as well as irbesartan reduced glomerular M/M invagination in nephriti c rats by approximately 30-50%. However, treatment with AT(1)-receptor antagonists did not influence binding of ATS to mesangial cells and s ubsequent complement activation indicating that the attenuated MCP-I e xpression is not due to differences in delivery and binding of ATS to mesangial cells, Conclusion: Our data indicate that short-term antagon ism of AT(1) receptors abolished the early glomerular MCP-1 expression and M/M influx. These results indicate that angiotensin II may exert immunomodulatory effects in vivo and adds a new mechanism showing how this vasopeptide may be involved in the pathogenesis of renal diseases .