title: PPARgamma-dependent regulation of adenylate cyclase 6 amplifies the stimulatory effect of cAMP on renin gene expression.
abstract: The second messenger cAMP plays an important role in the regulation of renin gene expression. Nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) is known to stimulate renin gene transcription acting through PPARγ-binding sequences in renin promoter. We show now that activation of PPARγ 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 PPARγ and mediated trans-activation by PPARγ agonist. AC6 knockdown decreased basal renin mRNA level and attenuated the maximal PPARγ-dependent stimulation of the cAMP-induced renin gene expression. AC6Pal3 decoy oligonucleotide abrogated the PPARγ-dependent potentiation of cAMP-induced renin gene expression. Treatment of mice with PPARγ agonist increased AC6 mRNA kidney levels. Our data suggest that in addition to its direct effect on renin gene transcription, PPARγ "sensitizes" renin gene to cAMP via trans-activation of AC6 gene. AC6 has been identified as PPARγ target gene with a functional Pal3 sequence.
authors.affiliation: Institute of Physiology, University of Regensburg, D-93040 Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Desch
authors.forename: Thomas
authors.initials: T
authors.lastname: Schubert
authors.forename: Andrea
authors.initials: A
authors.lastname: Schreiber
authors.forename: Sandra
authors.initials: S
authors.lastname: Mayer
authors.forename: Björn
authors.initials: B
authors.lastname: Friedrich
authors.forename: Ferruh
authors.initials: F
authors.lastname: Artunc
authors.forename: Vladimir T
authors.initials: VT
authors.lastname: Todorov
mesh_terms: D000262:Adenylyl Cyclases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D016384:Consensus Sequence; D000242:Cyclic AMP / Q000494:pharmacology*; D004357:Drug Synergism; D020536:Enzyme Activators / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007438:Introns / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D000077205:Pioglitazone; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012083:Renin / Q000235:genetics* / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D020536:Enzyme Activators; D009841:Oligonucleotides; D047495:PPAR gamma; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000242:Cyclic AMP; D012083:Renin; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; D000077205:Pioglitazone