An interaction of renin-angiotensin and kallikrein-kinin systems contributes to vascular hypertrophy in angiotensin II-induced hypertension: in vivo and in vitro studies

PLoS One. 2014 Nov 4;9(11):e111117. doi: 10.1371/journal.pone.0111117. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / toxicity
  • Animals
  • Antihypertensive Agents / pharmacology
  • Antihypertensive Agents / therapeutic use
  • Aorta / metabolism
  • Aorta / pathology
  • Blood Pressure / drug effects
  • Bradykinin B1 Receptor Antagonists / pharmacology
  • Cells, Cultured
  • Drug Synergism
  • Hypertension / drug therapy
  • Hypertension / metabolism
  • Hypertension / pathology*
  • Hypertrophy / metabolism
  • Kallikrein-Kinin System / drug effects
  • Kallikrein-Kinin System / physiology*
  • Losartan / pharmacology
  • Losartan / therapeutic use
  • Male
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / metabolism
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism
  • Receptor, Bradykinin B1 / agonists
  • Receptor, Bradykinin B1 / metabolism
  • Renin-Angiotensin System / drug effects
  • Renin-Angiotensin System / physiology*
  • Superoxides / metabolism

Substances

  • Antihypertensive Agents
  • Bradykinin B1 Receptor Antagonists
  • Reactive Oxygen Species
  • Receptor, Bradykinin B1
  • Superoxides
  • Angiotensin II
  • Losartan

Grants and funding

This work was support by grants from Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP - 200759278-7), Canadian Institute of Health Research (grant 44018), Conselho Nacional de Amparo a Pesquisa (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.