AT2 Receptor Activities and Pathophysiological Implications

Abstract

Although angiotensin II subtype-2 receptor (AT2R) was discovered over two decades ago, its contribution to physiology and pathophysiology is not fully elucidated. Current knowledge suggests that under normal physiologic conditions, AT2R counterbalances the effects of angiotensin II subtype-1 receptor (AT1R). A major obstacle for AT2R investigations was the lack of specific agonists. Most of the earlier AT2R studies were performed using the peptidic agonist, CG42112A, or the non-peptidic antagonist PD123319. CGP42112A is non-specific for AT2R and in higher concentrations can bind to AT1R. Recently, the development of specific non-peptidic AT2R agonists boosted the efforts in identifying the therapeutic potentials for AT2R stimulation. Unlike AT1R, AT2R is involved in vasodilation via release of bradykinin and nitric oxide, anti-inflammation and healing from injury. Interestingly, the vasodilatory effects of AT2R stimulation were not associated with significant reduction in blood pressure. In the kidney, AT2R stimulation produced natriuresis, increased renal blood flow, and reduced tissue inflammation. In animal studies, enhanced AT2R function led to reduction of cardiac inflammation and fibrosis, and reduced the size of the infarcted area. Similarly, AT2R stimulation demonstrated protective effects in vasculature and brain.

AT1 receptor signaling pathways in the cardiovascular system

“…These confusing results regarding AT2 receptor function is suggested to be largely dependent on expression levels of AT2 receptor in addition to Nox2 regulation and transforming growth factor beta 1 (TGFβ1) signaling pathways (17). The AT2 receptor will not be discussed further in this review, however, there are excellent review articles summarizing recent findings regarding the role of AT2 receptor in hypertension, vascular remodeling and cardiovascular dysfunction (9, 10, 18). …”

Small molecule and peptide therapies for chronic heart failure: a patent review (2011 – 2014)

“…Although the role of AT1R in the RAAS pathway is well-characterized, many of the physiological actions of AT2R have yet to be elucidated [91]. A peptide agonist, CGP42112A, has been known since 1989 [92], but lack of in vivo stability limited its use [93].…”

ISN Forefronts Symposium 2015: Maintaining Balance Under Pressure—Hypertension and the Proximal Tubule

“…6162 AngIII is the likely ligand for AT2R. 63 The Denton lab showed that direct stimulation of AT2R with the selective agonist C21 increases natriuresis and diuresis without changes in GFR or RBF, evidence for tubular actions.…”

“…Denton has demonstrated that the lower BP and more sensitive pressure natriuresis observed in WT female rodents is associated with 4 fold higher AT2R mRNA; 64 and that this sex advantage disappears with age and in global AT2R KO mice. 65 This fast growing area full of therapeutic potential 61,62 has a large gap in knowledge about how AT2R signaling affects sodium transporters/channels and intrarenal RAS in males and females.…”