Abstract


Background: Aldosterone secreted from adrenal gland is one of the most important hormones involved in the blood pressure regulation, and its increase contributes to the progression of resistant hypertension. The purpose of the study is to examine the effect of RXR agonist PA024 on adrenal aldosterone synthase gene (CYP11B2) expression as well as aldosterone secretion, and elucidate its molecular mechanisms for the future innovation of novel anti-hypertensive/anti-arteriosclerotic drugs. view more

Background: Aldosterone secreted from adrenal gland is one of the most important hormones involved in the blood pressure regulation, and its increase contributes to the progression of resistant hypertension. The purpose of the study is to examine the effect of RXR agonist PA024 on adrenal aldosterone synthase gene (CYP11B2) expression as well as aldosterone secretion, and elucidate its molecular mechanisms for the future innovation of novel anti-hypertensive/anti-arteriosclerotic drugs.
Methods and Materials: Angiotensin (A) II and RXR pan-agonist PA024 were used as reagents. We added various concentrations of PA024 on H295R cells derived from human adrenocortical carcinoma. We thereafter analyzed CYP11B2 mRNA expression by quantitative real-time PCR, CYP11B2 promoter activity by luciferase assay, aldosterone secretion by enzyme immunoassay, and intracellular Ca2+ level by Calcium Kit-Fluo 4, respectively.
Results: PA024 dose-dependently suppressed AII-induced CYP11B2 mRNA expression and CYP11B2 promoter activity. Additionally, high-dose PA024 significantly decreased aldosterone secretion. The suppression of CYP11B2 promoter activity by PA024 was observed in the deletion mutants analyses using the region from -1521 (full length) to -135 including NBRE-1, Ad4, and Ad5 elements. Therefore, transcription factors binding to these elements may be involved in the suppression. PA024 also suppressed mRNA expression of transcription factors Nurr1 and NGFIB in a dose-dependent manner. Since PA024-mediated suppression of CYP11B2 promoter activity was rescued by Nurr1 overexpression, decrease of Nurr1 expression may contribute to the suppression. On the other hand, PA024 did not affect on intracellular Ca2+ concentrations, cellular proliferation, and apoptosis. PA024 also inhibited mRNA expression of StAR, HSD3β2, and CYP21A2. Therefore, PA024-mediated suppression of these enzymes (and protein) may also be involved in the inhibition of aldosterone synthesis pathway.
Conclusions: These data indicate that RXR pan-agonist PA024 may possibly be a candidate of novel anti-hypertensive/anti-arteriosclerotic drugs via the suppression of aldosterone synthesis/secretion. We are currently investigating its in vivo effect using transgenic Tsukuba hypertensive mice (hRN8-12 x hAG2-5) which demonstrate AII-mediated CYP11B2 overexpression.

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