PPARγ ligand attenuates PDGF-induced mesangial cell proliferation: Role of MAP kinase

Abstract

Mesangial proliferation is a key feature in the pathogenesis of a number of renal diseases and can be experimentally induced by the mitogen platelet-derived growth factor (PDGF). Mitogen-activated protein kinase (MAPK) signaling plays a key role in mesangial cell proliferation. In the present study we examined whether peroxisome proliferator-activated receptor gamma (PPARgamma) activators/ligands, thiazolidinediones such as ciglitazone, troglitazone, and rosiglitazone, can inhibit cell proliferation by modulating individual steps in the MAPK pathway. Mouse mesangial cells were made quiescent and proliferation was measured following the application of PDGF. Using ciglitazone as the model compound, the mechanism of the antiproliferative effect of PPARgamma activators on MAPK and specific cell cycle regulatory proteins were examined by Western blot analysis and transfection studies. Ciglitazone inhibited PDGF-induced mesangial cell proliferation in a dose-dependent manner (1 to 20 micromol/L). The inhibitory effect was blocked by a peroxisome proliferator-activated receptor element (PPRE) decoy oligonucleotide, indicating that the observed effect of ciglitazone was via PPARgamma activation. Ciglitazone (1 to 20 micromol/L) did not affect extracellular signal-regulated protein kinase (ERK) activation but inhibited the activation of serum response element (SRE) by 85 +/- 6% (P < 0.01). This effect was associated with a reduction in c-fos expression (80 +/- 9%, P < 0.01). Ciglitazone (1, 10, and 20 micromol/L) also inhibited cyclin D1 expression by 37 +/- 8%, 79 +/- 15%, and 87 +/- 12%, respectively (P < 0.001 to 0.001), and p21 expression by 45 +/- 6% (P < 0.01), 61 +/- 10% (P < 0.001), and 72 +/- 8% (P < 0.001), respectively. Ciglitazone inhibited PDGF-mediated up-regulation of p27. In addition, the antiproliferative effect of ciglitazone was potentiated by PD98059, a mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor that acts at a step upstream from ERK. These data indicate that PPARgamma activation may inhibit mesangial growth directly by affecting MAPK and cell cycle regulatory proteins. Furthermore, a MAP kinase inhibitor can potentiate the antiproliferative effect.