Effects of different PPARgamma-agonists on MCP-1 expression and monocyte recruitment in experimental glomerulonephritis.
BACKGROUND
Activators of peroxisome proliferator activated receptor gamma (PPARgamma) have been shown to modulate chemokine expression in isolated monocytes/macrophages (M/M) and to exert anti-inflammatory effects in some models of experimental inflammatory diseases. We evaluated the effects of different forms of PPARgamma activators in a model of experimental glomerulonephritis (GN) in rats.


METHODS
GN was induced in rats by application of an anti-thymocyte antibody (ATS). Nephritic rats were treated with two synthetic PPARgamma ligands of the thiazolidinedione (TZD) group, troglitazone (200 mg/kg/day) and ciglitazone (100 mg/kg/day), and with a natural ligand 15d-PGJ2 (1.5 mg/day). Twenty-four hours after induction of the GN, the glomerular mRNA expression of the chemokine monocyte chemoattractant protein-1 (MCP-1) and the cognate chemokine receptor CCR-2 were examined by Northern blotting and RT-PCR. The glomerular M/M infiltration was determined by immunohistology. The activation of the transcription factors PPARgamma, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) in glomeruli was analyzed by electrophoretic mobility shift assay.


RESULTS
Induction of GN up-regulated glomerular nuclear protein binding of NF-kappaB and AP-1. Treatment of nephritic rats with troglitazone and ciglitazone augmented nuclear PPARgamma and AP-1 DNA binding but did not affect NF-kappaB binding. TZD enhanced glomerular MCP-1 expression and increased glomerular M/M recruitment. In contrast, 15d-PGJ2 attenuated NF-kappaB activation and did not affect AP-1 activity or MCP-1 expression.


CONCLUSIONS
Our data show that PPARgamma activators of the TZD group, but not 15d-PGJ2, enhance MCP-1 expression and M/M infiltration in the induction phase of experimental GN. The results demonstrate that TZD and 15d-PGJ2 may exert different effects in the immune response in experimental GN. Our study underscores the need to critically evaluate whether PPARgamma ligands will have beneficial or possibly deleterious effects in GN.
Zentrum für Innere Medizin, Medizinische Klinik IV, University of Hamburg, Hamburg, Germany.
Ulf
U
Panzer
André
A
Schneider
Youfei
Y
Guan
Rüdiger
R
Reinking
Gunther
G
Zahner
Sigrid
S
Harendza
Gunter
G
Wolf
Friedrich
F
Thaiss
Rolf A K
RA
Stahl
D000818:Animals; D002465:Cell Movement / Q000276:immunology; D018932:Chemokine CCL2 / Q000235:genetics*; D002839:Chromans / Q000494:pharmacology; D015870:Gene Expression / Q000276:immunology; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000276:immunology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology; D008297:Male; D009000:Monocytes / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism; D000077288:Troglitazone
C515336:Ccr2 protein, rat; D018932:Chemokine CCL2; D002839:Chromans; D007004:Hypoglycemic Agents; D016328:NF-kappa B; D009687:Nuclear Proteins; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000077288:Troglitazone