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Am J Physiol Renal Physiol 282: F639-F648, 2002. First published October 16, 2001; doi:10.1152/ajprenal.00189.2001
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Vol. 282, Issue 4, F639-F648, April 2002

Upregulation of type I collagen by TGF-beta in mesangial cells is blocked by PPARgamma activation

Feng Zheng1, Alessia Fornoni1, Sharon J. Elliot1, Youfei Guan2, Matthew D. Breyer2, Liliane J. Striker1, and Gary E. Striker1

1 Vascular Biology Institute and Division of Nephrology, Department of Medicine, University of Miami School of Medicine, Miami, Florida 33136; and 2 Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Vanderbilt, Tennessee 37232

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.

peroxisome proliferator-activated receptor-gamma ; transforming growth factor-beta 1; diabetic nephropathy


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