Update on angiotensin AT2 receptors

Abstract

Purpose of the review To update major new findings and concepts introduced during the past year on the role of angiotensin II (Ang II) subtype 2 receptors (AT2Rs) in the control of blood pressure (BP) and renal function. Recent findings AT2R activation prevents sodium (Na+) retention and lowers BP in the Ang II infusion model of experimental hypertension and prevents salt-sensitive hypertension in the obese Zucker rat model of obesity and the metabolic syndrome. Ang II metabolite, des-aspartyl1-Ang II (Ang III) is the predominant AT2R agonist in the kidney and possibly also in the vasculature; a novel synthetic Ang III peptide, β-Pro-Ang III, is vasodepressor and lowers BP in conscious spontaneously hypertensive rats (SHR) in the presence of low-level Ang II type 1 receptor (AT1R) blockade. Because nitric oxide (NO) is a product of AT2R activation, a potential feed forward loop, wherein NO increases AT2R transcription, may reinforce AT2R beneficial actions long term. AT2R activation also reduces proteinuria and oxidative stress in glomerulosclerotic kidneys of high salt obese Zucker rats. Summary Studies during the past year have helped clarify the physiological and pathophysiological roles of AT2Rs and have enhanced the promise of AT2R agonists in cardiovascular and renal disease.

The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases

“…While the angiotensinogen/renin/ACE/ANG II/AT 1 receptor axis acts as a “YANG” factor to induce vasoconstriction, increase blood pressure, and promote growth and fibrotic and proinflammatory responses, the APA/ANG III/AT 2 /cGMP axis acts as a “YIN” factor to counteract the vasopressor effect of ANG II/AT 1 activation to induce vasodilation and decrease blood pressure to maintain normal blood pressure homeostasis [25,95–97]. Before the AT 2 receptor was molecularly cloned, this class of ANG II receptors was primarily discriminated by using nonpeptide antagonists PD123177 and PD123319 or a peptide agonist CGP42112A in ANG II receptor binding assays [1,29,84,98].…”

“…The fundamental premise of therapeutically targeting the ANG II/APA/ANG III/AT 2 /cGMP axis is primarily based on the “YIN” and “YANG” balance hypothesis, in that as a “YANG” factor, the angiotensinogen/renin/ACE/ANG II/AT 1 receptor axis plays a key role in the pathogenesis of cardiovascular, hypertensive, diabetic and kidney diseases, whereas as an “YIN” factor, the ANG II/APA/ANG III/AT 2 /cGMP axis acts to counteract the detrimental effects of ANG II/AT 1 activation [25,95–97]. Indeed, one of the most successful stories in the drug development for cardiovascular, hypertensive, diabetic and kidney diseases during last three decades is the successful development of ACE inhibitors, ARBs, renin inhibitors, and aldosterone receptor antagonists to treat hypertension, ischemic heart disease or heart failure, and diabetic nephropathy in humans [72,74,115–117].…”

“…Unlike ANG II, both ANG III and ANG IV were previously considered partial agonists for ANG II receptors with lesser vasopressor activity [21–23]. More recently, ANG III has been recognized as a major ligand for the AT 2 receptor/NO/cGMP signaling cascade [18,24,25], whereas ANG IV is thought to activate the AT 4 receptor [23,26–28]. In late 1980s and early 1990s, through the study of ANG II receptor pharmacology it was discovered that ANG II acted on at least two different classes of G protein-coupled receptors, which led to the development of two classes of nonpeptide ANG II receptor antagonists, losartan as a representative blocker for type 1 (AT 1 ) and PD123319 as a representative type 2 (AT 2 ) receptor blockers [1,29–31].…”

“…ACE, which is primarily localized in the vascular endothelium of major target organs including lung, heart, kidney, adrenal glands, brain etc., converts ANG I to the most potent vasopressor of the RAS, ANG II, by removing two amino acids, His-Leu, from ANG I. ANG II acts on two classes of G protein-coupled receptors (GPCR), AT 1 and AT 2 and possibly the Mas-related G-protein-coupled receptor (MrgD) as well, to play important “YIN” and “YANG” counter-regulatory roles in maintaining normal cardiovascular, blood pressure and renal function, as well as in the development of cardiovascular, hypertensive and renal diseases [1,5,29,43]. In addition to the classic axis, the RAS has evolved well beyond its classic paradigms primarily as a powerful vasopressor, growth/fibrosis promoter, a potent aldosterone stimulator, or a sodium-retaining hormone [25,39,41,42]. New members of the RAS are continuously discovered with different roles during last few decades, so that ANG II is no longer the only active peptide of the RAS.…”

“…However, overactivation of these two axes of the RAS plays a critical role in the development of cardiovascular and kidney diseases and hypertension. By contrast, the other two axes of the RAS, including the ANG II/APA/ANG III/AT 2 /NO/cGMP axis [24,25,45] and the ANG I/ANG II/ACE2/ANG (1–7)/ Mas receptor axis [39–42] may serve as the vasodepressor and cardiorenal protective arms of the RAS acting to counteract the detrimental effects of the renin/ACE/ANG II/AT 1 receptor axis and the prorenin/renin/PRR/MAP kinases ERK1/2/V-ATPase axis. The ANG III/APN/ANG IV/IRAP/AT 4 receptor axis is unlikely classified as an independent member of the vasopressor or vasodepressor system, since it appears to play a primary role in learning and memory [26,31,38].…”