AT1-receptor antagonists abolish glomerular MCP-1 expression in a model of mesangial proliferative glomerulonephritis

Exp Nephrol. Mar-Apr 1998;6(2):112-20. doi: 10.1159/000020513.


Background: Glomerular accumulation of macrophages/monocytes (M/M) is a typical early feature in the course of anti-thymocyte serum (ATS)-induced nephritis. We have previously shown that glomerular synthesis and expression of monocyte-chemoattractant protein-1 (MCP-1) occurs before influx of M/M and a neutralizing anti-MCP-1 antibody reduced this cell infiltrate by one third. The present study was undertaken to test the effect of two angiotensin II type 1 (AT1) 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 losartan or irbesartan was started 24 h before administration of ATS. After 24 h, MCP-1 mRNA expression was evaluated by RT-PCR and Northern blots. MCP-1 protein was determined by Western blots and chemotactic factors released from isolated glomeruli were measured by chemotactic assay. Kidney sections were stained for rabbit IgG, complement C3, and M/M (ED1 antigen).

Results: Both AT1-receptor antagonists caused a significant, but not total reduction in MCP-1 mRNA and protein expression 24 h after injection of ATS. Treatment with losartan or irbesartan also reduced the chemotactic activity of isolated glomeruli from nephritic animals. Quantification of ED1-positive cells revealed that losartan as well as irbesartan reduced glomerular M/M invagination in nephritic rats by approximately 30-50%. However, treatment with AT1-receptor antagonists did not influence binding of ATS to mesangial cells and subsequent complement activation indicating that the attenuated MCP-1 expression is not due to differences in delivery and binding of ATS to mesangial cells.

Conclusion: Our data indicate that short-term antagonism of AT1 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin Receptor Antagonists*
  • Animals
  • Antibodies / pharmacology
  • Antihypertensive Agents / pharmacology*
  • Antilymphocyte Serum
  • Biphenyl Compounds / pharmacology*
  • Chemokine CCL2 / biosynthesis*
  • Gene Expression Regulation / drug effects*
  • Glomerulonephritis, Membranoproliferative / chemically induced
  • Glomerulonephritis, Membranoproliferative / metabolism*
  • Glomerulonephritis, Membranoproliferative / pathology
  • Immunoglobulin G / analysis
  • Irbesartan
  • Kidney Glomerulus / drug effects
  • Kidney Glomerulus / metabolism*
  • Kidney Glomerulus / pathology
  • Losartan / pharmacology*
  • Male
  • Polymerase Chain Reaction
  • Rabbits
  • Rats
  • Rats, Inbred Lew
  • Rats, Wistar
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Renin / blood
  • Tetrazoles / pharmacology*


  • Angiotensin Receptor Antagonists
  • Antibodies
  • Antihypertensive Agents
  • Antilymphocyte Serum
  • Biphenyl Compounds
  • Chemokine CCL2
  • Immunoglobulin G
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Tetrazoles
  • Renin
  • Irbesartan
  • Losartan