Upregulation of type I collagen by TGF-beta in mesangial cells is blocked by PPARgamma activation.
We found that peroxisome proliferator-activated receptor-gamma (PPARgamma) mRNA was reduced by 77% in glomeruli of diabetic mice. Because mesangial cells play an important role in diabetic nephropathy, we examined regulation of type I collagen expression by PPARgamma and transforming growth factor-beta(1) (TGF-beta(1)) in mouse mesangial cells in the presence of 6 and 25 mM glucose. Mesangial cells contained functionally active PPARgamma. Exposure to 25 mM glucose resulted in reduced PPARgamma expression and transcriptional activity, accompanied by increased type I collagen expression. Restoration of PPARgamma activity to normal levels in cells cultured in 25 mM glucose, by transfection with a PPARgamma expression construct and treatment with the PPARgamma agonist troglitazone, returned type I collagen levels toward normal values. Activation of PPARgamma by troglitazone also decreased type I collagen mRNA and blocked TGF-beta(1)-mediated upregulation of type I collagen mRNA and protein. Moreover, PPARgamma activation suppressed basal and activated TGF-beta(1) responses in mesangial cells. This action was blocked by transfection of cells with a dominant-negative PPARgamma construct. In summary, PPARgamma suppresses the increased type I collagen mRNA and protein expression mediated by TGF-beta(1) in mesangial cells.
Zheng
Feng
F
Vascular Biology Institute and Division of Nephrology, Department of Medicine, University of Miami School of Medicine, Miami, Florida 33136, USA. fzheng@med.miami.edu
Fornoni
Alessia
A
Elliot
Sharon J
SJ
Guan
Youfei
Y
Breyer
Matthew D
MD
Striker
Liliane J
LJ
Striker
Gary E
GE
D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D024042:Collagen Type I / Q000096:biosynthesis* / Q000235:genetics; D003920:Diabetes Mellitus / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D024042:Collagen Type I; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D005947:Glucose