Overexpression of Kinin B1 Receptors Induces Hypertensive Response to Des-Arg9-bradykinin and Susceptibility to Inflammation

• Published in: The Journal of biological chemistry Vol. 278; no. 1; pp. 219 - 225
• Main Authors: Ni, Aiguo, Yin, Hang, Agata, Jun, Yang, Zhirong, Chao, Lee, Chao, Julie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.01.2003; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Sequence; Animals; Blood Pressure - drug effects; Blood Pressure - physiology; Bradykinin - analogs & derivatives; Bradykinin - metabolism; Bradykinin - pharmacology; Carrageenan - toxicity; Cell Line; Female; Humans; Inflammation - chemically induced; Inflammation - metabolism; Inositol Phosphates - metabolism; Ligands; Lipopolysaccharides - pharmacology; Mice; Mice, Transgenic; Molecular Sequence Data; Mutation; Promoter Regions, Genetic; Protein Structure, Secondary; Rats; Receptor, Bradykinin B1; Receptors, Bradykinin - genetics; Receptors, Bradykinin - metabolism; Second Messenger Systems - physiology; Survival Rate; Transgenes
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M209490200

We demonstrated that rat kinin B1 receptors displayed a ligand-independent constitutive activity, assessed through inositol phosphate production in transiently or stably transfected human embryonic kidney 293A cells. Substitution of Ala for Asn130 in the third transmembrane domain resulted in additional constitutive activation of the B1 receptor. The constitutively active mutant N130A receptor could be further activated by the B1 receptor agonist des-Arg9-bradykinin. To gain insights into the physiological function of the B1 receptor, we have generated transgenic mice overexpressing wild-type and constitutively active mutant receptors under the control of human cytomegalovirus immediately early gene enhancer/promoter. The rat B1receptor transgene expression was detected in the aorta, brain, heart, lung, liver, kidney, uterus, and prostate of transgenic mice by reverse transcription-polymerase chain reaction/Southern blot analysis. Transgenic mice were fertile and normotensive. Overexpression of B1 receptors exacerbated paw edema induced by carrageenan and rendered transgenic mice more susceptible to lipopolysaccharide-induced endotoxic shock. Interestingly, the hemodynamic response to kinins was altered in transgenic mice, with des-Arg9-bradykinin inducing blood pressure increase when intravenously administered. Our study supports an important role for B1 receptors in modulating inflammatory responses and for the first time demonstrates that B1 receptors mediate a hypertensive response to des-Arg9-bradykinin.