Overexpression of kinin B1 receptors induces hypertensive response to des-Arg9-bradykinin and susceptibility to inflammation.
We demonstrated that rat kinin B(1) 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 Asn(130) in the third transmembrane domain resulted in additional constitutive activation of the B(1) receptor. The constitutively active mutant N130A receptor could be further activated by the B(1) receptor agonist des-Arg(9)-bradykinin. To gain insights into the physiological function of the B(1) 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 B(1) receptor 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 B(1) 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-Arg(9)-bradykinin inducing blood pressure increase when intravenously administered. Our study supports an important role for B(1) receptors in modulating inflammatory responses and for the first time demonstrates that B(1) receptors mediate a hypertensive response to des-Arg(9)-bradykinin.
Ni
Aiguo
A
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Yin
Hang
H
Agata
Jun
J
Yang
Zhirong
Z
Chao
Lee
L
Chao
Julie
J
D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D002351:Carrageenan / Q000633:toxicity; D002460:Cell Line; D005260:Female; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007295:Inositol Phosphates / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D017433:Protein Structure, Secondary; D051381:Rats; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin / Q000235:genetics / Q000378:metabolism*; D015290:Second Messenger Systems / Q000502:physiology; D015996:Survival Rate; D019076:Transgenes
D007295:Inositol Phosphates; D008024:Ligands; D008070:Lipopolysaccharides; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin; C024626:bradykinin, des-Arg(9)-; D002351:Carrageenan; D001920:Bradykinin