The effect of high glucose and PPAR- agonists on PPAR- expression and function in HK-2 cells

Panchapakesan, U., C. A. Pollock, and X. M. Chen. The effect of high glucose and PPARagonists on PPARexpression and function in HK-2 cells. Am J Physiol Renal Physiol 287: F528–F534, 2004. First published April 27, 2004; 10.1152/ajprenal.00445.2003.— Peroxisome proliferator-activated receptor(PPAR) are ligandactivated transcription factors that regulate cell growth, inflammation, lipid metabolism, and insulin sensitivity. PPARin the human kidney has been described. However, the role of PPARin 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 M), and the selective PPARagonist L-805645 (8 M) on PPARexpression, growth, and inflammatory parameters in the proximal tubular model of HK-2 cells. PPARwas present in HK-2 cells and upregulated with 30 mM D-glucose to 177 31.2% of control (P 0.05). PPARactivation 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 p21 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 factor1 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 PPARand when significantly induced demonstrates anti-proliferative and anti-inflammatory effects.