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PPAR agonists exert antifibrotic effects in renal tubular cells exposed to high glucose

Department of Medicine, University of Sydney, and Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, New South Wales, Australia

Submitted 10 March 2005 ; accepted in final form 1 May 2005

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; Panchapakesan U, Pollock CA, and Chen XM. Am J Physiol Renal Physiol 287: F528–F534, 2004). However, the role of PPAR in the excess extracellular matrix production is largely unknown. We evaluated the effect of 24- to 48-h 8 µM L-805645 or 10 µM 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)-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-B to 167 ± 22.4% (P < 0.05), which was not modified with PPAR agonists. In conclusion, PPAR agonists exert antifibrotic effects in human PTC in high glucose by attenuating the increase in AP-1, TGF-₁, and the downstream production of the extracellular matrix protein fibronectin.

thiazolidinediones; diabetic nephropathy; proximal tubular cells

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