Effects of Azilsartan on PPAR Gamma Gene Expression and Oxidative Stress in 3T3 L1 Cells

The metabolic syndrome is a condition that is characterized by a clustering of factors including insulin resistance, dyslipidemia, central obesity, and/or hypertension. This syndrome has no known cause but a dysfunctional renin angiotensin system (RAS), a hormonal system that regulates blood pressure and water balance, is thought to contribute to the pathogenesis of several features of the metabolic syndrome including hypertension and insulin resistance. One class of RAS inhibitors, angiotensin II type I receptor blockers (ARBs), may include a subset of molecules with enhanced potential for reducing the risk of diabetes in patients with hypertension and the metabolic syndrome. Specifically, some ARBs have been identified that activate the peroxisome proliferator activated receptor gamma (PPARy) which is an intracellular transcription factor that controls the expression of genes involved in glucose and lipid metabolism. Azilsartan is a recently developed ARB that has been shown to increase PPARy gene expression in adipose tissue in vivo. Whether this increase is a direct effect of PPARy activation or an indirect effect is unknown. We investigated whether azilsartan could directly increase PPARy gene expression in adipocytes in vitro. We found that azilsartan had no effect gene expression of PPARy in cultured adipocytes but did increase mRNA accumulation of some down-stream target genes. Protein levels were unchanged as detected by semi-quantitative immunoblots. There was a small increase, roughly 10%, of reactive oxygen species within the mitochondria of 3T3 L1 adipocytes following azilsartan exposure. Our study suggests that azilsartan has no effect on PPARy gene expression in vitro but does increase the mRNA transcript levels of several downstream targets within the PPARy signaling pathway.