AT1-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)-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.


CONCLUSIONS
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.
Wolf
G
G
Department of Medicine, University Hospital Eppendorf, Hamburg, Germany. Wolf@UKE.Uni-Hamburg.de
Schneider
A
A
Helmchen
U
U
Stahl
R A
RA
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000961:Antilymphocyte Serum; D001713:Biphenyl Compounds / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000187:drug effects*; D015432:Glomerulonephritis, Membranoproliferative / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007074:Immunoglobulin G / Q000032:analysis; D000077405:Irbesartan; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D016133:Polymerase Chain Reaction; D011817:Rabbits; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012083:Renin / Q000097:blood; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000906:Antibodies; D000959:Antihypertensive Agents; D000961:Antilymphocyte Serum; D001713:Biphenyl Compounds; D018932:Chemokine CCL2; D007074:Immunoglobulin G; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D012083:Renin; D000077405:Irbesartan; D019808:Losartan