Peroxisome proliferator-activated receptor-γ ligands inhibit TGF-β1-induced fibronectin expression in glomerular mesangial cells

The thiazolidinedione (TZD) class of antidiabetic drugs, which are ligands for peroxisome proliferator-activated receptor (PPAR)-gamma, has been shown to possess potent anti-inflammatory and antineoplastic actions. Here, we show in mesangial cells that PPAR-gamma agonists inhibit fibronectin expression by transforming growth factor (TGF)-beta1. TGF-beta1 enhanced fibronectin mRNA expression, and this enhancement was abrogated by pretreatment with pioglitazone. Electrophoretic mobility shift assay identified that pioglitazone inhibited TGF-beta1-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-beta1-induced activation of mitogen-activated protein kinases (MAPKs) or Smad2. PPAR-gamma overexpression inhibited TGF-beta1-induced fibronectin expression as well as the activation of AP-1. 15-Deoxy-Delta(12,14)- prostaglandin J(2) (15d-PGJ(2)), a natural PPAR-gamma ligand, also inhibited TGF-beta1-induced fibronectin expression by suppressing AP-1 activation by TGF-beta1. 15d-PGJ(2) inhibited the TGF-beta1-induced MAPK activation. Dominant-negative PPAR-gamma (DeltaPPAR-gamma) completely abrogated the inhibitory effect of pioglitazone and incompletely blocked its effect of 15d-PGJ(2) on TGF-beta1-induced AP-1 reporter activity. DeltaPPAR-gamma overexpression did not affect the inhibitory effect of 15d-PGJ(2) on TGF-beta1-induced MAPK activation. In conclusion, pioglitazone inhibits TGF-beta1-induced fibronectin expression by inhibiting AP-1 activation dependent on PPA-R-gamma, while 15d-PGJ(2) acts through a dual mechanism independent of and dependent on PPA-R-gamma activation in mouse mesangial cells.