Kinin B₁receptor upregulation by angiotensin II and endothelin-1 in rat vascular smooth muscle cells: receptors and mechanisms

Abstract

Oxidative stress upregulates the kinin B(1) receptor (B(1)R) in diabetes and hypertension. Since angiotensin II (ANG II) and endothelin-1 (ET-1) are increased in these disorders, this study aims at determining the role of these two prooxidative peptides in B(1)R expression in rat vascular smooth muscle cells (VSMC). In the A10 cell line and aortic VSMC, ANG II enhanced B(1)R protein expression in a concentration- and time-dependent manner (maximal at 1 μM and 6 h). In A10 cells, ANG II (1 μM) also increased B(1)R mRNA expression at 3 h and the activation of induced B(1)R with the agonist [Sar-d-Phe(8)]-des-Arg(9)-BK (10 nM, 5 min) significantly enhanced mitogen-activated protein kinase (MAPK1/2) phosphorylation. The enhancing effect of ANG II on B(1)R protein expression in A10 cells was normalized by the AT(1) (losartan) but not by the AT(2) (PD123319) receptor antagonist. Furthermore, it was inhibited by inhibitors of phosphatidylinositol 3-kinase (wortmannin) and NF-κB (MG132) but not of MAPK (PD098059). Whereas the ET(B) receptor antagonist (BQ788) had no effect, the ET(A) receptor antagonist (BQ123) blocked the effect of ANG II at 6-8 h but not at an early time point. BQ123 and BQ788 also blocked the increasing effect of ET-1 on B(1)R protein expression. Antioxidants (N-acetyl-l-cysteine and diphenyleneiodonium) abolished ANG II- and ET-1-increased B(1)R protein expression. In conclusion, B(1)R induction is linked to oxidative stress and activation of phosphatidylinositol 3-kinase and NF-κB. The newly synthesized B(1)R is functional and can activate MAPK signaling in VSMC. The effect of ANG II is mediated by the AT(1) receptor and the subsequent activation of ET(A) through ET-1 release.

Role of integrins in angiotensin II-induced proliferation of vascular smooth muscle cells

“…*P Ͻ 0.05, **P Ͻ 0.01 vs. vehicle. induced ERK activation, published previously by our group (26), and has been reported as optimal to study AII-induced protein expression in cultured VSMC (13,24). No significant changes in any integrin messages, including ␣ 1 -, ␣ 5 -, or ␤ 1 -integrin subunits, were detected in VSMC treated with AII compared with vehicle-treated cells (not shown).…”

The kallikrein–kinin system in diabetic nephropathy

“…B2R is constitutively expressed in most tissues, including all segments of the kidney, and it mediates the majority of the physiological effects of kinins in health. In contrast, B1R is expressed at only low levels under physiological conditions, but its expression is induced by various pathological stimuli such as ischemia-reperfusion injury (50), proinflammatory cytokines (51,52), diabetes (53), bacterial endotoxins (54), and angiotensin II (55), implying an important role of B1R activation under pathological situations. The cytokine-induced upregulation of B1R is mainly regulated by mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) (51,56,57).…”

Long-term endothelin receptor antagonism attenuates coronary plaque progression in patients with early atherosclerosis

“…In experimental studies this ET-1 effect was blocked by the ET-A-receptor antagonist, a specific inhibitor of the IkappaB-alpha-degrading proteasome complex and also prevented NF-kappa B activation thus demonstrating the ability of ET-1 to activate inflammatory pathways in human macrophages[36]. .Previous studies have also demonstrated that ET A receptor antagonist block the effect of endothelin-1 on kinin B 1 receptor expression which is associated with oxidative stress[37]. Thus blocking the inflammatory process and oxidative stress may be a potential mechanism contributing to the attenuation of plaque progression with ET A receptor antagonism in the study.…”