Essential Role of AT _1A Receptor in the Development of 2K1C Hypertension

Abstract

Abstract-The aims of this study were to delineate the relative contribution of angiotensin II (ANG II) subtype 1A (AT 1A ) and 1B (AT 1B ) receptors to the development of two-kidney, one-clip (2K1C) Goldblatt hypertension in mice, to examine if increased nitric oxide synthase (NOS) activity counteracts the vasoconstrictor influences of ANG II in 2K1C hypertensive mice, and to determine the role of ANG II type 2 (AT 2 ) receptors in 2K1C hypertension in mice. AT 1A ANG II receptor knockout (AT 1A Ϫ/Ϫ) and wild-type (AT 1A ϩ/ϩ) mice underwent clipping of the right renal artery. Systolic blood pressure (SBP) was significantly lower in AT 1A Ϫ/Ϫ compared with AT 1A ϩ/ϩ mice, and neither clip placement nor AT 2 receptor blockade with PD 123319 (PD) altered SBP in AT 1A Ϫ/Ϫ mice. A significant and sustained rise in SBP from 119Ϯ5 to 163Ϯ6 mm Hg was observed in the 2K1C AT 1A ϩ/ϩ mice from day 10 to day 26. Chronic PD infusion did not alter the course of hypertension in 2K1C/AT 1A ϩ/ϩ. Acute PD infusion did not alter mean arterial Key Words: mice Ⅲ receptors, angiotensin II Ⅲ hypertension, renovascular Ⅲ nitric oxide synthase Ⅲ nitric oxide I t is well recognized that the renin-angiotensin system plays the pivotal role in the development and maintenance of two-kidney, one-clip (2K1C) Goldblatt hypertension. 1 Previous studies have shown that activation of angiotensin II (ANG II) type 1 (AT 1 ) receptors predominantly mediates the effect of ANG II on the renal vasculature and is largely responsible for the development of hypertension in ANG II-dependent models of hypertension. 2-4 However, two subtypes for AT 1 receptors have been identified in mouse and rat (AT 1A and AT 1B ). 5 It has been demonstrated that the AT 1A receptors are the predominant subtype in most tissues, with the exception of the adrenal cortex, pituitary gland, and glomerulus, where the AT 1B receptors are also highly expressed. 6,7 The critical role of AT 1A receptors in blood pressure (BP) regulation has been confirmed by the development of AT 1A receptor knockout mice (AT 1A Ϫ/Ϫ). The AT 1A Ϫ/Ϫ mice exhibit markedly lower BP and impaired ability for normal sodium handling by the kidney and urinary concentrating ability compared with their wild-type controls (AT 1A ϩ/ϩ). 8 -11 In contrast, the AT 1B receptor knockout mice (AT 1A Ϫ/Ϫ) exhibit no abnormal phenotype. 12 However, it has been shown that in the absence of AT 1A receptors, AT 1B receptors may partially replace the function of AT 1A receptors in BP regulation. 13 Moreover, it has been also demonstrated that when AT 1A receptors are absent, AT 1B receptors can play an important role in mediating ANG II effects in the renal vasculature. 14,15 Taken together, these results indicate that under certain conditions, AT 1B receptors partially compensate for the absence of AT 1A receptors. In view of this information, we hypothesized that activation of AT 1B might contribute to the development of 2K1C Goldblatt hypertension. Since the binding signatures of the AT 1A and AT 1B receptors are ident...

Intrarenal angiotensin II and angiotensinogen augmentation in chronic angiotensin II-infused mice

“…It is also possible that high doses of ANG II facilitate interactions with other receptors, like AT 2 R and megalin, that may counteract AT 1 R actions. However, in the case of the AT 2 R, findings by Cervenka et al (4) and Wesseling et al (37) point out that it is unlikely that AT 2 R activation contributes significantly to the ANG II-mediated increases in arterial pressure during ANG II-dependent hypertension.…”

In vivo regulation of AT1a receptor-mediated intracellular uptake of [125I]Val5-ANG II in the kidneys and adrenals of AT1a receptor-deficient mice

“…These responses may be interpreted by two different cellular mechanisms. First, total deletion of AT 1a receptors would lead to loss of all known responses to extracellular ANG II that are attributable to cell surface AT 1 receptors (6,7,14,17). This mechanism likely plays a predominant role in Agtr1aϪ/Ϫ mice (7,14).…”

Altered Release of Cytochrome P450 Metabolites of Arachidonic Acid in Renovascular Disease

“…Although PRA decreases soon after the development of renal artery stenosis, 4 Ang II still represents a primary stimulus via activation of Ang II type 1 receptor for the release of a number of bioactive compounds, including aldosterone, endothelin, and eicosanoids, 30 dently contribute to vasoconstriction, salt and water retention, vascular remodeling, renal fibrosis, and the decline in glomular filtration rate that ultimately determines the progression of the disease. 4 Furthermore, studies on 2-kidney, 1-clip renovascular hypertension in rats have shown that blocking the renin-angiotensin system prevented hypertension indefinitely.…”