Peroxisome proliferator-activated receptor- suppresses CYP11B2 expression and aldosterone production

Abstract

Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear receptor for the antidiabetic agent thiazolidinedione, which exerts various physiological activities, independent of lowering blood glucose. However, the role of PPARγ in aldosterone production has not been clarified. The objective of this study was to investigate the effect of PPARγ on aldosterone synthase gene (CYP11B2) expression and aldosterone production. Localization of PPARγ expression in normal adrenal cortex was determined by immunohistochemistry. Aldosterone production and CYP11B2 expression levels were determined using human adrenocortical carcinoma H295R cells. Pioglitazone suppressed angiotensin II-induced aldosterone secretion and CYP11B2 expression. PPARγ was expressed in zona glomerulosa in human normal adrenal gland. PPARγ overexpression enhanced pioglitazone-mediated CYP11B2 transrepression. The pioglitazone-mediated suppression of aldosterone secretion and CYP11B2 expression were canceled by PPARγ L466A/E469A mutant. Pioglitazone also suppressed potassium-mediated CYP11B2 induction, but not N6-2'-O-dibutyladenosine-3',5'-cyclic monophosphate stimulation. Rosiglitazone and GW1929 also suppressed CYP11B2 transactivation. Mutation analysis revealed that the Ad1/CRE element in CYP11B2 5'-flanking region was responsible for the pioglitazone-mediated transrepression. Pioglitazone suppressed ionomycin and a truncated constitutively active form Ca(2+)/calmodulin-dependent kinase I (CaMKI)-mediated CYP11B2 transcriptional activation. A CaMK inhibitor KN-93 attenuated pioglitazone-mediated CYP11B2 transrepression. PPARγ suppresses CYP11B2 expression and aldosterone secretion.