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1Divisions of Endocrinology-Diabetes-Medical Genetics and Nephrology, Department of Medicine, Medical University of South Carolina, and 2Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina 29425
Submitted 6 August 2003 ; accepted in final form 3 November 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—9-10—6 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—7 M. ANG II (10—7 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 (AT1 receptor antagonist) and/or PD-123319 (AT2 receptor antagonist) at 10 µM for 30 min, followed by ANG II (10—7 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 AT1A 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/p44mapk (PD-98059) and/or an inhibitor of p38mapk (SB-202190), followed by ANG II (10—7 M) for 24 h. Selective inhibition of the p42/p44mapk 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.
AT1 receptors; mitogen-activated protein kinase; vascular smooth muscle cells
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