Peroxisome Proliferator-Activated Receptor-γ Ligands Inhibit TGF-β1-Induced Fibronectin Expression in Glomerular Mesangial Cells

Abstract

The thiazolidinedione (TZD) class of antidiabetic drugs, which are ligands for peroxisome proliferator-activated receptor (PPAR)-γ, has been shown to possess potent anti-inflammatory and antineoplastic actions. Here, we show in mesangial cells that PPAR-γ agonists inhibit fibronectin expression by transforming growth factor (TGF)-β1. TGF-β1 enhanced fibronectin mRNA expression, and this enhancement was abrogated by pretreatment with pioglitazone. Electrophoretic mobility shift assay identified that pioglitazone inhibited TGF-β1-induced DNA binding of activator protein-1 (AP-1). Pioglitazone inhibited AP-1 reporter activity but not Smad binding elements reporter activity without affecting TGF-β1-induced activation of mitogen-activated protein kinases (MAPKs) or Smad2. PPAR-γ overexpression inhibited TGF-β1-induced fibronectin expression as well as the activation of AP-1. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a natural PPAR-γ ligand, also inhibited TGF-β1-induced fibronectin expression by suppressing AP-1 activation by TGF-β1. 15d-PGJ2 inhibited the TGF-β1-induced MAPK activation. Dominant-negative PPAR-γ (ΔPPAR-γ) completely abrogated the inhibitory effect of pioglitazone and incompletely blocked its effect of 15d-PGJ2 on TGF-β1-induced AP-1 reporter activity. ΔPPAR-γ overexpression did not affect the inhibitory effect of 15d-PGJ2 on TGF-β1-induced MAPK activation. In conclusion, pioglitazone inhibits TGF-β1-induced fibronectin expression by inhibiting AP-1 activation dependent on PPAR-γ, while 15d-PGJ2 acts through a dual mechanism independent of and dependent on PPAR-γ activation in mouse mesangial cells.