title: An interaction of renin-angiotensin and kallikrein-kinin systems contributes to vascular hypertrophy in angiotensin II-induced hypertension: in vivo and in vitro studies.
abstract: The kallikrein-kinin and renin-angiotensin systems interact at multiple levels. In the present study, we tested the hypothesis that the B1 kinin receptor (B1R) contributes to vascular hypertrophy in angiotensin II (ANG II)-induced hypertension, through a mechanism involving reactive oxygen species (ROS) generation and extracellular signal-regulated kinase (ERK1/2) activation. Male Wistar rats were infused with vehicle (control rats), 400 ng/Kg/min ANG II (ANG II rats) or 400 ng/Kg/min ANG II plus B1 receptor antagonist, 350 ng/Kg/min des-Arg(9)-Leu(8)-bradykinin (ANGII+DAL rats), via osmotic mini-pumps (14 days) or received ANG II plus losartan (10 mg/Kg, 14 days, gavage - ANG II+LOS rats). After 14 days, ANG II rats exhibited increased systolic arterial pressure [(mmHg) 184 ± 5.9 vs 115 ± 2.3], aortic hypertrophy; increased ROS generation [2-hydroxyethidium/dihydroethidium (EOH/DHE): 21.8 ± 2.7 vs 6.0 ± 1.8] and ERK1/2 phosphorylation (% of control: 218.3 ± 29.4 vs 100 ± 0.25]. B1R expression was increased in aortas from ANG II and ANG II+DAL rats than in aortas from the ANG II+LOS and control groups. B1R antagonism reduced aorta hypertrophy, prevented ROS generation (EOH/DHE: 9.17 ± 3.1) and ERK1/2 phosphorylation (137 ± 20.7%) in ANG II rats. Cultured aortic vascular smooth muscle cells (VSMC) stimulated with low concentrations (0.1 nM) of ANG II plus B1R agonist exhibited increased ROS generation, ERK1/2 phosphorylation, proliferating-cell nuclear antigen expression and [H3]leucine incorporation. At this concentration, neither ANG II nor the B1R agonist produced any effects when tested individually. The ANG II/B1R agonist synergism was inhibited by losartan (AT1 blocker, 10 µM), B1R antagonist (10 µM) and Tiron (superoxide anion scavenger, 10 mM). These data suggest that B1R activation contributes to ANG II-induced aortic hypertrophy. This is associated with activation of redox-regulated ERK1/2 pathway that controls aortic smooth muscle cells growth. Our findings highlight an important cross-talk between the DABK and ANG II in the vascular system and contribute to a better understanding of the mechanisms involved in vascular remodeling in hypertension.
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil; Department of Physiological Sciences, Biological Sciences Center, State University of Londrina, Londrina, Brazil.
authors.forename: Graziela S
authors.initials: GS
authors.lastname: Ceravolo
authors.affiliation: Ottawa Health Research Institute, Kidney Research Centre, University of Ottawa, Ottawa, Canada; BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Montezano
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences III, University of São Paulo, Sao Paulo, Brazil.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Jordão
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Eliana H
authors.initials: EH
authors.lastname: Akamine
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Tiago J
authors.initials: TJ
authors.lastname: Costa
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences III, University of São Paulo, Sao Paulo, Brazil.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Takano
authors.affiliation: Vascular Biology Laboratory, Heart Institute, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Denise C
authors.initials: DC
authors.lastname: Fernandes
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences III, University of São Paulo, Sao Paulo, Brazil.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Barreto-Chaves
authors.affiliation: Vascular Biology Laboratory, Heart Institute, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Francisco R
authors.initials: FR
authors.lastname: Laurindo
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Zuleica B
authors.initials: ZB
authors.lastname: Fortes
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences III, University of São Paulo, Sao Paulo, Brazil.
authors.forename: Renato P
authors.initials: RP
authors.lastname: Chopard
authors.affiliation: Ottawa Health Research Institute, Kidney Research Centre, University of Ottawa, Ottawa, Canada; BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Maria Helena C
authors.initials: MH
authors.lastname: Carvalho
mesh_terms: D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D065169:Bradykinin B1 Receptor Antagonists / Q000494:pharmacology; D002478:Cells, Cultured; D004357:Drug Synergism; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006984:Hypertrophy / Q000378:metabolism; D016234:Kallikrein-Kinin System / Q000187:drug effects / Q000502:physiology*; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D043783:Receptor, Bradykinin B1 / Q000819:agonists / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D065169:Bradykinin B1 Receptor Antagonists; D017382:Reactive Oxygen Species; D043783:Receptor, Bradykinin B1; D013481:Superoxides; D000804:Angiotensin II; D019808:Losartan