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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^*

^* 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

Address correspondence to: Dr. Samir S. El-Dahr, Department of Pediatrics, SL-37, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112. Phone: 504-988-377; Fax: 504-988-1852; E-mail: seldahr{at}tulane.edu

Received for publication October 18, 2006. Accepted for publication January 25, 2007.

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.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673