Dept. of Medicine, University of Sydney, Royal North Shore Hospital, NSW 2065, Australia.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) are ligand-activated transcription factors that regulate cell growth, inflammation, lipid metabolism, and insulin sensitivity. We recently demonstrated that PPARgamma agonists limit high glucose-induced inflammation in a model of proximal tubular cells (PTC; Panchapakesan U, Pollock CA, and Chen XM. Am J Physiol Renal Physiol 287: F528-F534, 2004). However, the role of PPARgamma in the excess extracellular matrix production is largely unknown. We evaluated the effect of 24- to 48-h 8 microM l-805645 or 10 microM pioglitazone on 25 mM D-glucose-induced markers of fibrosis in HK-2 cells. High D-glucose induced nuclear binding of activator protein-1 (AP-1) to 140.8 +/- 10.9% (P < 0.05), which was attenuated with L-805645 and pioglitazone to 82.3 +/- 14.4 (P < 0.01 vs. high D-glucose) and 99.3 +/- 12.2% (P < 0.05 vs. high D-glucose), respectively. High D-glucose increased total production of transforming growth factor (TGF)-beta(1) 139.6 +/- 6.5% (P < 0.05), which was reversed with L-805645 and pioglitazone to 68.73 +/- 5.7 (P < 0.01 vs. high D-glucose) and 112 +/- 13.6% (P < 0.05 vs. high D-glucose). L-805645 and pioglitazone reduced high d-glucose-induced fibronectin from 156.0 +/- 24.9 (P < 0.05) to 81.9 +/- 16.0 and 57.4 +/- 12.7%, respectively (both P < 0.01 vs. high D-glucose). Collagen IV was not induced by high d-glucose. L-805645 and pioglitazone suppressed collagen IV to 68.0 +/- 14.5 (P < 0.05) and 46.5 +/- 11.6% (P < 0.01) vs. high D-glucose, respectively. High D-glucose increased the nuclear binding of NF-kappaB to 167 +/- 22.4% (P < 0.05), which was not modified with PPARgamma agonists. In conclusion, PPARgamma agonists exert antifibrotic effects in human PTC in high glucose by attenuating the increase in AP-1, TGF-beta(1), and the downstream production of the extracellular matrix protein fibronectin.