Vascular Type 1A Angiotensin II Receptors Control BP by Regulating Renal Blood Flow and Urinary Sodium Excretion

Abstract

Inappropriate activation of the type 1A angiotensin (AT 1A ) receptor contributes to the pathogenesis of hypertension and its associated complications. To define the role for actions of vascular AT 1A receptors in BP regulation and hypertension pathogenesis, we generated mice with cell-specific deletion of AT 1A receptors in smooth muscle cells (SMKO mice) using Loxp technology and Cre transgenes with robust expression in both conductance and resistance arteries. We found that elimination of AT 1A receptors from vascular smooth muscle cells (VSMCs) caused a modest (approximately 7 mmHg) yet significant reduction in baseline BP and exaggerated sodium sensitivity in mice. Additionally, the severity of angiotensin II (Ang II)-dependent hypertension was dramatically attenuated in SMKO mice, and this protection against hypertension was associated with enhanced urinary excretion of sodium. Despite the lower BP, acute vasoconstrictor responses to Ang II in the systemic vasculature were largely preserved (approximately 80% of control levels) in SMKO mice because of exaggerated activity of the sympathetic nervous system rather than residual actions of AT 1B receptors. In contrast, Ang II-dependent responses in the renal circulation were almost completely eliminated in SMKO mice (approximately 5%-10% of control levels). These findings suggest that direct actions of AT 1A receptors in VSMCs are essential for regulation of renal blood flow by Ang II and highlight the capacity of Ang II-dependent vascular responses in the kidney to effect natriuresis and BP control.

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…ANG II has a direct effect on renal VSMCs, causing vasoconstriction of afferent and efferent arterioles, resulting in reduced renal blood flow, favoring sodium reabsorption. The role of renal vascular AT 1 R in reducing RBF and contributing to ANG II-induced hypertension has been recently confirmed with VSMC AT 1A R-deficient mice (987). A few studies suggest a contribution of oxidative stress in ANG II-enhanced vasoconstriction of afferent arterioles (569).…”

“…In these studies with Cre-loxP technology, Sm22␣ Cre, Tie2 Cre, or S100A4 Cre driver was used to knockout smooth muscle, endothelial, or fibroblast AT 1A R. Vascular smooth muscle AT 1A R was found to be dispensable for ANG II increasing blood pressure (986). However, in a recent study, using Cre transgenes with robust expression in both conductance and resistance arteries (Sm22␣ Cre knock in), it appears that vascular smooth AT 1A R deficiency is preventive against ANG II-induced elevation in blood pressure, which is associated with increased urinary sodium excretion and decreased vasoconstrictor responses in the renal vasculature (987). Tie2 Cre is known to be expressed in hematopoietic cells, and S100A4 expression in vascular smooth muscle cells was also reported (163).…”

AT1 receptor signaling pathways in the cardiovascular system

“…AT1 receptor in VSMCs is essential for AngII-mediated regulation of renal blood flow, and mice with VSMC specific AT1 receptor depletion show increased urinary sodium excretion and attenuated AngII-induced high blood pressure (158). Mice with principal cell specific AT1 receptor depletion show enhanced natriuresis and a modest decrease in blood pressure in the initial phase of AngII-dependent hypertension (159).…”

Resistance to hypertension mediated by intercalated cells of the collecting duct

“…COX-2 inhibition selectively reduces medullary blood flow in mice and induces an exaggerated pressor response to angiotensin II (24). Such alterations in renal blood flow can affect blood pressure homeostasis, since changes in medullary blood flow significantly impact sodium excretion (37)(38)(39). On the other hand, prostanoids generated by COX-2 may also directly impact sodium and fluid reabsorption by renal epithelial cells (40).…”