Rosiglitazone prevents high glucose-induced vascular endothelial growth factor and collagen IV expression in cultured mesangial cells.
Peroxisome proliferator-activated receptor (PPARgamma), a ligand-dependent transcription factor, negatively modulates high glucose effects. We postulated that rosiglitazone (RSG), an activator of PPARgamma 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 5.6 mM (NG) or 25 mM D-glucose (HG) for up to 48 hours. In HG, PPARgamma 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 PPARgamma 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, PPARgamma 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.
Whiteside
Catharine
C
Department of Medicine, University Health Network, Toronto, ON, Canada. whiteside@utoronto.ca
Wang
Hong
H
Xia
Ling
L
Munk
Snezana
S
Goldberg
Howard J
HJ
Fantus
I George
IG
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D008566:Membranes / Q000737:chemistry; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D019255:NADPH Oxidases / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014162:Transfection; D000077288:Troglitazone; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D002839:Chromans; D024141:Collagen Type IV; D047495:PPAR gamma; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D042461:Vascular Endothelial Growth Factor A; D000077154:Rosiglitazone; D019255:NADPH Oxidases; C086986:CYBA protein, human; D011493:Protein Kinase C; D055372:AMP-Activated Protein Kinases; D000077288:Troglitazone; D005947:Glucose; C039671:ciglitazone