Inhibitory effects of peroxisome proliferator-activated receptor gamma agonists on collagen IV production in podocytes

摘要

Peroxisome proliferator-activated receptor-c (PPAR-c) agonists have beneficial effects on the kidney diseases through preventing microalbuminuria and glomerulosclerosis. However, the mechanisms underlying these effects remain to be fully understood. In this study, we investigate the effects of PPAR-gamma agonist, rosiglitazone (Rosi) and pioglitazone (Pio), on collagen IV production in mouse podocytes. The endogenous expression of PPAR-gamma was found in the primary podocytes and can be upregulated by Rosi and Pio, respectively, detected by RT-PCR and Western blot. PPAR-gamma agonist markedly blunted the increasing of collagen IV expression and extraction in podocytes induced by TGF-beta. In contrast, adding PPAR-gamma antagonist, GW9662, to podocytes largely prevented the inhibition of collagen IV expression from Pio treatment. Our data also showed that phosphorylation of Smad2/3 enhanced by TGF-beta in a time-dependent manner was significantly attenuated by adding Pio. The promoter region of collagen IV gene contains one putative consensus sequence of Smad-binding element (SBE) by promoter analysis, Rosi and Pio significantly ameliorated TGF-beta-induced SBE4-luciferase activity. In conclusion, PPAR-gamma activation by its agonist, Rosi or Pio, in vitro directly inhibits collagen IV expression and synthesis in primary mouse podocytes. The suppression of collagen IV production was related to the inhibition of TGF-beta-driven phosphorylation of Smad2/3 and decreased response activity of SBEs of collagen IV in PPAR-gamma agonist-treated mouse podocytes. This represents a novel mechanistic support regarding PPAR-gamma agonists as podocyte protective agents.