PPARγ-Dependent Regulation of Adenylate Cyclase 6 Amplifies the Stimulatory Effect of cAMP on Renin Gene Expression

The second messenger cAMP plays an important role in the regulation of renin gene expression. Nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR gamma) is known to stimulate renin gene transcription acting through PPAR gamma-binding sequences in renin promoter. We show now that activation of PPAR gamma by unsaturated fatty acids or thiazolidinediones drastically augments the cAMP-dependent increase of renin mRNA in the human renin-producing cell line Calu-6. The underlying mechanism involves potentiation of agonist-induced cAMP increase and up-regulation of adenylate cyclase 6 (AC6) gene expression. We identified a palindromic element with a 3-bp spacer (Pal3) in AC6 intron 1 (AC6Pal3). AC6Pal3 bound PPAR gamma and mediated trans-activation by PPAR gamma agonist. AC6 knockdown decreased basal renin mRNA level and attenuated the maximal PPAR gamma-dependent stimulation of the cAMP-induced renin gene expression. AC6Pal3 decoy oligonucleotide abrogated the PPAR gamma-dependent potentiation of cAMP-induced renin gene expression. Treatment of mice with PPAR gamma agonist increased AC6 mRNA kidney levels. Our data suggest that in addition to its direct effect on renin gene transcription, PPAR gamma "sensitizes" renin gene to cAMP via trans-activation of AC6 gene. AC6 has been identified as PPAR gamma target gene with a functional Pal3 sequence. (Molecular Endocrinology 24: 2139-2151, 2010)