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) Agonists on PPAR Expression and Function in HK-2 Cells
1 Department of Medicine, University of Sydney, Renal Research Group, Kolling Institute of Medical Research, 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. 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, the thiazolidinedione pioglitazone (10µM) and the selective PPAR agonist L-805645 (8µM) 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 mM 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 mM 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 value < 0.0001). 30 mM D-glucose induced TGF
1 to 137.7 ± 16.9% of control (p value < 0.05) and L-805645 was able to suppress this to 68.7 ± 5.7% of control (p value < 0.01 vs D-glucose). Exposure to 30 mM D-glucose reduced MCP-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 antiproliferative and anti-inflammatory effects.
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