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agonists on PPAR- expression and function in HK-2 cells
Department of Medicine, The University of Sydney, Renal Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, New South Wales 2065, Australia
Submitted 18 December 2003 ; accepted in final form 22 April 2004
Peroxisome proliferator-activated receptor-
(PPAR-) are ligand-activated transcription factors that regulate cell growth, inflammation, lipid metabolism, and insulin sensitivity. PPAR- in the human kidney has been described. However, the role of PPAR- in proximal tubular cells with respect to cell growth and inflammation in diabetic nephropathy is largely unknown. We evaluated the effect of high (30 mM) D-glucose, thiazolidinedione pioglitazone (10 µM), and the selective PPAR- agonist L-805645 (8 µM) on PPAR- expression, growth, and inflammatory parameters in the proximal tubular model of HK-2 cells. PPAR- was present in HK-2 cells and upregulated with 30 mM D-glucose to 177 ± 31.2% of control (P < 0.05). PPAR- activation was induced by pioglitazone to a similar level to that observed by exposure to high glucose but maximally induced by the selective agonist L-805645. However, L-805645 reduced cell viability in both 5 and 30 mM D-glucose to 73.8 ± 3.1 and 77.6 ± 1.4% of control (both P < 0.0001). In parallel, thymidine incorporation was reduced with L-805645 in both 5 and 30 mM D-glucose to 33.3 ± 3.4 and 37.9 ± 2.2%, respectively (both P < 0.0001). Flow cytometry demonstrated increased apoptosis and G1 phase arrest in association with an increase in p21cip1/waf1 in cells exposed to L-805645. Exposure to 30 mM D-glucose did not significantly change AP-1 promoter activity (89.0 ± 5.5% of control); however, the addition of L-805645 significantly reduced it to 62.2 ± 2.7% of control (P < 0.0001). Thirty nanomolar D-glucose induced transforming growth factor-
1 to 137.7 ± 16.9% of control (P < 0.05), and L-805645 was able to suppress this to 68.7 ± 5.7% of control (P < 0.01 vs. D-glucose). Exposure to 30 mM D-glucose reduced monocyte chemoattractant protein 1 levels to 78.6 ± 7.1% (P < 0.05) of control, with the reduction more marked in the presence of either pioglitazone (P < 0.01) or L-805645 (P < 0.01). In summary, high glucose upregulates PPAR- and when significantly induced demonstrates anti-proliferative and anti-inflammatory effects.
diabetic nephropathy; proximal tubular cells; cell cycle; thiazolidinediones
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