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1 Dept. of Medicine, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia
* To whom correspondence should be addressed. E-mail: carpol{at}med.usyd.edu.au.
Peroxisome proliferator-activated receptor 
(PPAR) are ligand activated transcription factors that regulate cell growth, inflammation, lipid metabolism and insulin sensitivity. We recently demonstrated that PPAR agonists limit high glucose-induced inflammation in a model of proximal tubular cells (PTC). However, the role of PPAR in the excess extracellular matrix production produced by PTC under high glucose conditions is largely unknown. We evaluated the effect of 24 to 48 hours 8µM L-805645 (a selective non-thiazolidinedione PPAR agonist) or 10µM Pioglitazone (a thiazolidinedione PPAR agonist) on high (25mM) D-glucose induced markers of fibrosis compared to control (5mM D-glucose) in the proximal tubular model of HK-2 cells. High glucose induced nuclear binding of activator protein-1 (AP-1) to 140.8 ± 10.9 % of control values (P<0.05), which was attenuated in the presence of L-805645 and Pioglitazone to 82.3 ± 14.4 % of control (P<0.01 vs high D-glucose) and 99.3 ± 12.2% of control (P<0.05 vs high D-glucose) respectively. Downstream transforming growth factor 
1 (TGF1) showed parallel changes with high glucose increasing total production of TGF1 to 4.8 pg/ml or 139.6 ± 6.5% of control (P<0.05), which was reversed in the presence of L-805645 and Pioglitazone (2.93 pg/ml or 68.73 ± 5.7% (P<0.01 vs. high D-glucose) and 3.77 pg/ml or 112 ± 13.6% (P<0.05 vs high D-glucose). L-805645 and Pioglitazone also reduced the high D-glucose-induced increase in fibronectin expression from 156.0 ± 24.9% of control (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, however L-805645 and pioglitazone suppressed collagen IV levels 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
B to 167 ± 22.4% of control (P<0.05), which was not modified in the presence of either PPAR agonist. In conclusion, PPAR agonists exert antifibrotic effects in human proximal tubular cells under high glucose conditions by attenuating the increase in AP-1, TGF1 and the downstream production of the extracellular matrix protein fibronectin.
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