Angiotensin Receptors and Aging

Abstract

T he major biological actions of the renin-angiotensin system are mediated by angiotensin (Ang) II, which binds with equal affinity to Ang type 1 (AT 1 ) and type 2 (AT 2 ) receptors. The majority of Ang II actions, however, are mediated by the AT 1 receptor, including vasoconstriction, cellular proliferation, tissue growth, direct renal tubular sodium reabsorption, sympathetic nervous stimulation, and aldosterone secretion, which, in aggregate, lead to a rise in blood pressure. 1 Because the AT 1 receptor is expressed ubiquitously in relatively high levels at renal and cardiovascular sites, an increase in blood pressure represents the net response to increased circulating Ang II.By contrast, AT 2 receptors carry a relatively low level of tissue expression in the adult compared with that of AT 1 receptors. 1 AT 2 receptors are expressed in large quantities in fetal tissues, but their expression decreases in the neonatal period and reaches a comparatively low level in the adult animal. However, the capacity for AT 2 receptor re-expression is retained in the adult, because upregulation is a common response to circumstances of cardiovascular tissue damage, such as myocardial infarction, heart failure, and hypertension.Activation of AT 2 receptors by the binding of Ang II stimulates a hormonal cascade consisting of bradykinin (BK), NO, and cGMP, leading to vasodilation that is counterregulatory to the vasoconstriction induced by Ang II via AT 1 receptors. 2 AT 2 receptor-induced vasodilation has been unequivocally demonstrated in both resistance and capacitance vessels. 3,4 In capacitance vessels, Ang II binding to the AT 2 receptor activates the BK B 2 receptor, stimulating the phosphorylation of endothelial NO synthase at its serine 633 and serine 1177 residues by a protein kinase A-dependent mechanism, inducing NO generation. 4 In mesenteric, uterine, and coronary small resistance arteries, Ang II-induced vasodilation is mediated by the BK/NO/cGMP pathway and is not subject to desensitization, as is AT 1 receptor-mediated vasoconstriction. In whole-animal studies, in the presence of AT 1 receptor blockade, Ang II induces sustained vasodilation and hypotension that is abolished by AT 2 receptor antagonist PD-123319 and is mediated by the BK/NO/cGMP pathway. 5,6 Thus, it is now generally accepted that the AT 2 receptor induces counterregulatory vasodilation that opposes AT 1 receptor-mediated vasoconstriction.Because AT 2 receptor expression is developmentally regulated, and its activation has been described as inhibitory to flow-mediated dilation in hypertensive animals, Pinaud et al,7 in this issue, hypothesized that AT 2 receptor function might behave differently in the resistance arteries of aged rats compared with nonaged control adult rats. As expected, their results show that resistance arteries from old rats had lower flow-and NO-mediated vasodilation and lower endothelial NO synthase expression than that of young control rats. However, a surprising finding was that, in old rats, AT 2 receptor blockade impr...

Mechanism of attenuation of pro-inflammatory Ang II-induced NF-κB activation by genistein in the kidneys of male rats during aging

“…These results agree with previous reports Carey 2007) and strongly support that AT1 is the most important pro-inflammatory mediator on Ang II-induced inflammation during aging. Interestingly, AT1-deficient mice growup normally and outlive their wild-type littermates by 26% and these mice also develop fewer aortic atherosclerotic lesions and less cardiac injury during Intracellular RS levels were measured by DCF-DA using a fluorescent probe using microscopy (Motic) (b).…”

“…With advancing age, oxidative alterations accumulate in cellular components, including those in the anti-oxidative defense systems, due to disrupted redox regulation during aging can influence the gene transcription and signal transduction pathways (Harman 1973;Chung et al 2006;Yu and Chung 2006). Recent evidence from AT1-deficient mice indicates that disruption of AT1 promotes longevity through the attenuation of oxidative stress , and completely protects against the age-related progression of atherosclerosis (Carey 2007).…”

Inhibition of NF-κB-induced inflammatory responses by angiotensin II antagonists in aged rat kidney

“…Indeed, Ang II generates reactive species (RS) during the inflammatory response via multiple signaling pathways [Cheng et al, 2005, Sachse & Wolf 2007, Kang et al, 2008] involving activation of the Ang II type 1 receptor (AT1) [Carey et al, 2007]. Several cell culture studies suggest that Ang II itself induces O 2 − production which is rapidly converted to H 2 O 2 , a pro-inflammatory mediator [Zafari et al, 1998].…”

Angiotensin II type 1 and type 2 receptor expression in circulating monocytes of diabetic and hypercholesterolemic patients over 3-month rosuvastatin treatment

“…Very few studies are at present published on the AT 2 R expression and functioning in humans, and it is now generally accepted that the AT 1 R blockade is associated with AT 2 R overexpression and that AT 2 R stimulation by Ang II induces counterregulatory vasodilatation that opposes AT 1 R–mediated vasoconstriction [28]. Indeed, in a study on resistance arteries dissected from gluteal subcutaneous tissues of hypertensive diabetic patients treated with valsartan, Ang II evoked a significant vasodilatory response which was blocked by an AT 2 R inhibitor [6].…”