TY - JOUR
T1 - Overexpression of kinin B1 receptors induces hypertensive response to Des-Arg9-bradykinin and susceptibility to inflammation
AU - Ni, Aiguo
AU - Yin, Hang
AU - Agata, Jun
AU - Yang, Zhirong
AU - Chao, Lee
AU - Chao, Julie
PY - 2003/1/3
Y1 - 2003/1/3
N2 - 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 B1 receptor transgene expression was detected in the aorta, brain, heart, lung, liver, kidney, uterus, and prostate of transgenic mice by reverse transcriptionpolymerase 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.
AB - 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 B1 receptor transgene expression was detected in the aorta, brain, heart, lung, liver, kidney, uterus, and prostate of transgenic mice by reverse transcriptionpolymerase 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.
UR - http://www.scopus.com/inward/record.url?scp=0037414639&partnerID=8YFLogxK
U2 - 10.1074/jbc.M209490200
DO - 10.1074/jbc.M209490200
M3 - Article
C2 - 12411434
AN - SCOPUS:0037414639
SN - 0021-9258
VL - 278
SP - 219
EP - 225
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 1
ER -