Received October 18, 2006
Accepted on January 25, 2007

BASIC SCIENCE ARTICLES: Genetics and Development

The Bradykinin B2 Receptor Gene Is a Target of Angiotensin II Type 1 Receptor Signaling

Bing Shen ^*, Lisa M. Harrison-Bernard , Andrew J. Fuller , Vanessa Vanderpool ^*, Zubaida Saifudeen ^*, and Samir S. El-Dahr ^*1

*Department of Pediatrics, Section of Pediatric Nephrology, Department of Physiology, Tulane University Health Sciences Center, and Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana

¹ To whom correspondence should be addressed. E-mail: seldahr{at}tulane.edu.

	Abstract

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 II (AngII) type 1 receptor (AT₁R) in collecting duct cells. AngII induced BdkrB2 mRNA expression in mouse inner medullary collecting duct cells, and this effect was abrogated by AT₁R blockade; in contrast, AT₂R 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 AT₁-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 AT₁R-CREB signaling pathway. Transcriptional regulation represents a novel form of cross-talk between GPCR that link the renin-angiotensin and kallikrein-kinin systems.