Mechanisms of angiotensin II-induced expression of B₂kinin receptors

Abstract

Tan, Yan, Florence N. Hutchison, and Ayad A. Jaffa. Mechanisms of angiotensin II-induced expression of B2 kinin receptors. Am J Physiol Heart Circ Physiol 286: H926-H932, 2004; 10.1152/ ajpheart.00757.2003.-Although the primary roles of the kallikreinkinin system and the renin-angiotensin system are quite divergent, they are often intertwined under pathophysiological conditions. We examined the effect of ANG II on regulation of B2 kinin receptors (B2KR) in vascular cells. Vascular smooth muscle cells (VSMC) were treated with ANG II in a concentration (10 Ϫ9 -10 Ϫ6 M)-and time (0-24 h)-dependent manner, and B2KR protein and mRNA levels were measured by Western blots and PCR, respectively. A threefold increase in B2KR protein levels was observed as early as 6 h, with a peak response at 10 Ϫ7 M. ANG II (10 Ϫ7 M) also increased B2KR mRNA levels twofold 4 h after stimulation. Actinomycin D suppressed the increase in B2KR mRNA and protein levels induced by ANG II. To elucidate the receptor subtype involved in mediating this regulation, VSMC were pretreated with losartan (AT 1 receptor antagonist) and/or PD-123319 (AT 2 receptor antagonist) at 10 M for 30 min, followed by ANG II (10 Ϫ7 M) stimulation. Losartan completely blocked the ANG II-induced B2KR increase, whereas PD-123319 had no effect. In addition, expression of B2KR mRNA levels was decreased in AT 1A receptor knockout mice. Finally, to determine whether ANG II stimulates B2KR expression via activation of the MAPK pathway, VSMC were pretreated with an inhibitor of p42/ p44 mapk (PD-98059) and/or an inhibitor of p38 mapk (SB-202190), followed by ANG II (10 Ϫ7 M) for 24 h. Selective inhibition of the p42/p44 mapk pathway significantly blocked the ANG II-induced increase in B2KR expression. These findings demonstrate that ANG II regulates expression of B2KR in VSMC and provide a rationale for studying the interaction between ANG II and bradykinin in the pathogenesis of vascular dysfunction.AT 1 receptors; mitogen-activated protein kinase; vascular smooth muscle cells THE KALLIKREIN-KININ SYSTEM (KKS) and the renin-angiotensin system (RAS) have been implicated in the regulation of renal and cardiovascular function and in the control of blood pressure. Although the primary roles of these two systems under physiological conditions are quite divergent, they often function in concert with each other under pathological conditions such as renal and cardiovascular disease (10,13,14,33). The two systems can interact and influence the activity of each other at many levels. In this regard, angiotensin-converting enzyme (ACE, kininase II), which converts ANG I to ANG II, also mediates the catabolism of bradykinin (BK; Ref. 44). In addition, treatment of nephrotic rats with enalapril induces the expression of renal kallikrein mRNA levels and increases the excretion rate of urinary kallikrein, thus providing a direct link between kallikrein and ACE inhibitors (10). Recent findings have identified that prolylcarboxypeptidase activates plasma prekallikrein to kallikrein and is ...

Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin

“…27,43 Stimulation of AT 2 R leads to BK and NO formation, preventing myocardial injury and also resulting in increased expression of the BK B2 receptor in vascular smooth muscle. 34,38 Further, NO production in the kidney in the BKB2R Ϫ/Ϫ mice is mediated by the AT 2 R. 35 Our investigations indicate that in the absence of the BKB2R in mice, there is probable reduced BK uptake into cells and increased plasma prekallikrein, RPPGF, and AngII ( Figure 6). The BKB1R is slightly overexpressed in BKB2R KO mice, as previously reported, but it does not contribute to the thrombosis protection seen since an agonist to it does not elevate tPA.…”

“…Recent evidence suggests that the bradykinin receptors and the angiotensin receptors may interact and regulate each other at the level of the receptor. 34,38,39 However, ascribing thromboprotection to AngII presents a paradox. Usually, elevations of AngII are associated with vasoconstriction and increased thrombosis risk due to elevated PAI-1 and tissue factor.…”

“…The BKB1R is slightly overexpressed in BKB2R KO mice, as previously reported, but it does not contribute to the thrombosis protection seen since an agonist to it does not elevate tPA. 38,44 The elevated AngII in the BKB2R KO mice probably binds to an overexpressed AT 2 R to contribute to thrombosis protection ( Figure 6). What regulates AT 2 R expression in these mice is not known, but as already indicated, the bradykinin and AT receptors interact.…”

Angiotensin II Type 2 Receptor–Bradykinin B 2 Receptor Functional Heterodimerization

“…This finding is consistent with recent studies examining the effects angiotensin II on the regulation of B 2 receptors. 23 The reverse was also observed between AT 1 R and kallikrein gene therapy. 24 The maximum increase in AT 2 R-B 2 R heterodimer formation was observed as a result of combined treatment of an AT 2 R agonist and a B 2 R antagonist, each individually increasing the expression of both receptors and inducing a 250% increase in heterodimer formation.…”

The Bradykinin B2 Receptor Gene Is a Target of Angiotensin II Type 1 Receptor Signaling

“…Infusion of subpressor dosages of AngII upregulates cardiac myocyte BdkrB2 gene expression in mice (6). Furthermore, treatment of vascular smooth muscle cells in culture with AngII produces a time-dependent induction of BdkrB2 mRNA, an effect that is inhibited by AT 1 R blockade (7). However, the mechanisms whereby AngII regulates BdkrB2 gene expression are not fully understood, and whether AT 1 R-B2R cross-talk operates in other AngII target tissues, such as the kidney, is not entirely clear.…”