l-165041 and Hyperglycemia

Diabetic nephropathy is the leading cause of end-stage renal disease in the most developed countries of the world. Hyperglycemia-induced advanced glycation end products (AGEs) and receptor for AGEs (RAGE) production, pro-inflammatory cytokine secretion, and oxidative stress activation play major roles in kidney cell injury and apoptosis. Peroxisome proliferator-activated receptor-gamma (PPARγ) agonists are used clinically as insulin sensitizers. This study evaluated the renoprotective effect of PPARγ (troglitazone) and PPARδ (L-165,041) agonists on human embryonic kidney 293 (HEK) and mesangial cells. Troglitazone (10 μM) and L-165,041 (1 μM) significantly inhibited high glucose (25mM)-induced interleukin-6 and TNF-α production, RAGE expression and NF-κB translocation in HEK cells. Furthermore, Troglitazone (10 μM) and L-165,041(1 μM) significantly increased SOD expression and attenuated apoptosis in HEK and mesangial cells. The inhibitory effect between 1 μM L-165,041 and 10 μM troglitazone showed no difference. Furthermore L-165,041 and troglitazone together did not increase the effects. These results provide important information for future application of PPAR agonists in diabetic nephropathy treatment.

Topics: Apoptosis; Chromans; Cytokines; Drug Interactions; Gene Expression Regulation; Glucose; HEK293 Cells; Humans; Hyperglycemia; NF-kappa B; Oxidative Stress; Phenoxyacetates; PPAR delta; PPAR gamma; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Thiazolidinediones; Troglitazone