The bradykinin B2 receptor gene is a target of angiotensin II type 1 receptor signaling

Cross-talk between G protein-coupled receptors (GPCR) is known to occur at multiple levels, including receptor heterodimerization and intracellular signaling. This study tested the hypothesis that GPCR cross-talk occurs at the transcriptional level. It was demonstrated that the bradykinin B2 receptor gene (BdkrB2) is a direct transcriptional target of the angiotensin 11 (AngII) type 1 receptor (AT(1)R) in collecting duct cells. AngII induced BdkrB2 mRNA expression in mouse inner medullary collecting duct cells, and this effect was abrogated by AT(1)R blockade; in contrast, AT(2)R blockade was ineffective. Actinomycin D, an inhibitor of gene transcription, abrogated AngII-stimulated BdkrB2 expression. In addition, AngII produced dosage- and time-dependent increases in B2 receptor protein levels (2.9 +/- 0.4 fold; P < 0.05). AngII stimulated phosphorylation of cAMP response element binding protein (CREB) on Ser-133 and assembly of p-CREB on the BdkrB2 promoter in vivo. Moreover, AngII induced hyperacetylation of BdkrB2 promoter-associated H4 histones, a chromatin modification that is associated with gene activation. Mutations of the CRE abrogated AngII-induced activation of the BdkrB2 promoter. AngII-treated inner medullary collecting duct cells exhibited augmented intracellular calcium signaling in response to bradykinin, confirming the functional relevance of AT(1)-B2 receptor signaling. Finally, studies that were conducted in angiotensin type 1 receptor (Agtr1)-null mice revealed that BdkrB2 mRNA levels were significantly lower in the renal medulla of Agtr1(A)(-/-) and Agtr1(A/B)(-/-) than in Agtr1(+/+) and Agtr1(B)(-/-) mice. It is concluded that BdkrB2 is a downstream target of the AT(1)R-CREB signaling pathway. Transcriptional regulation represents a novel form of cross-talk between GPCR that link the renin-angiotensin and kallikrein-kinin systems.