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 II (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.
Shen
Bing
B
Department of Pediatrics, SL-37, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
Harrison-Bernard
Lisa M
LM
Fuller
Andrew J
AJ
Vanderpool
Vanessa
V
Saifudeen
Zubaida
Z
El-Dahr
Samir S
SS
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D008297:Male; D051379:Mice; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D043782:Receptor, Bradykinin B2 / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology*; D015533:Transcriptional Activation
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D044140:Receptor, Angiotensin, Type 1; D043782:Receptor, Bradykinin B2; D000804:Angiotensin II; D003609:Dactinomycin; D002118:Calcium