Rosiglitazone prevents high glucose-induced vascular endothelial growth factor and collagen IV expression in cultured mesangial cells.

Peroxisome proliferator-activated receptor (PPAR gamma), a ligand-dependent transcription factor, negatively modulates high glucose effects. We postulated that rosiglitazone (RSG), an activator of PPAR gamma prevents the upregulation of vascular endothelial growth factor (VEGF) and collagen IV by mesangial cells exposed to high glucose. Primary cultured rat mesangial cells were growth-arrested in 5.6mM (NG) or 25mM D-glucose (HG) for up to 48 hours. In HG, PPAR gamma mRNA and protein were reduced within 3 h, and enhanced ROS generation, expression of p22(phox), VEGF and collagen IV, and PKC-zeta membrane association were prevented by RSG. In NG, inhibition of PPAR gamma caused ROS generation and VEGF expression that were unchanged by RSG. Reduced AMP-activated protein kinase (AMPK) phosphorylation in HG was unchanged with RSG, and VEGF expression was unaffected by AMPK inhibition. Hence, PPAR gamma is a negative modulator of HG-induced signaling that acts through PKC-zeta but not AMPK and regulates VEGF and collagen IV expression by mesangial cells. Copyright (C) 2009 Catharine Whiteside et al.