Effects of different PPARγ-agonists on MCP-1 expression and monocyte recruitment in experimental glomerulonephritis

Abstract

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. 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. 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. 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.