The angiotensin AT2 receptor stimulates protein tyrosine phosphatase activity and mediates inhibition of particulate guanylate cyclase

doi:10.1016/0006-291X(92)91629-5

Biochemical and Biophysical Research Communications

Volume 183, Issue 1, 28 February 1992, Pages 206-211

https://doi.org/10.1016/0006-291X(92)91629-5 Get rights and content

Abstract

The signalling mechanism and cellular targets of the AT₂ receptor are still unknown. We report that angiotensin II (Ang II) inhibits basal and atrial natriuretic peptide stimulated particulate guanylate cyclase (pGC) activity through AT₂ receptors in rat adrenal glomerulosa and PC12W cells. This inhibition is blocked by the phosphotyrosine phosphatase (PTPase) inhibitor orthovanadate but not by the $Ser Thr$ phosphatase inhibitor okadaic acid, suggesting the involvement of a PTPase in this process. Moreover, Ang II induces a rapid, transient and orthovanadate sensitive dephosphorylation of phosphotyrosine containing proteins in PC12W cells. Our findings suggest that AT₂ receptors signal through stimulation of a PTPase and that this mechanism is implicated in the regulation of pGC activity. This observation is also the first example of hormonal inhibition of basal pGC activity.

References (27)

S Whitebread et al.
Biochem. Biophys. Res. Commun
(1989)
A.T. Chiu et al.
Biochem. Biophys. Res. Commun
(1989)
S. Jard et al.
J. Biol. Chem
(1981)
S.P. Bottari et al.
Eur. J. Pharmacol. Mol. Pharmacol. Sect
(1991)
R.C. Speth et al.
Biochem. Biophys. Res. Commun
(1990)
B.J. Ballermann et al.
Biochem. Biophys. Res. Commun
(1988)
J.A. Gordon
P. Cohen et al.
Trends Biochem. Sci
(1990)
R.B. Marala et al.
FEBS Lett
(1991)
R.S.L. Chang et al.
Mol. Pharmacol
(1990)

K. Sasaki et al.

Nature

(1991)

T.J. Murphy et al.

Nature

(1991)

H Glossman et al.

J. Biol. Chem

(1974)

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AT2 receptor stimulation inhibits phosphate-induced vascular calcification
2019, Kidney International
Citation Excerpt :
Previous reports have suggested that angiotensin II stimulates Wnt/β-catenin signals through AT1,42,43 and AT2 stimulation also affects Wnt/β-catenin signals.44 Furthermore, AT2 stimulation has also been reported to enhance various phosphatase activity.45,46 Therefore, a possible mechanism via inhibition of Wnt/β-catenin activity and phosphorylation of ERK23 is involved.
Vascular calcification is a common finding in atherosclerosis and in patients with chronic kidney disease. The renin-angiotensin system plays a role in the pathogenesis of cardiovascular remodeling. Here, we examined the hypothesis that angiotensin II type 2 receptor (AT2) stimulation has inhibitory effects on phosphate-induced vascular calcification. In vivo, calcification of the thoracic aorta induced by an adenine and high-phosphate diet was markedly attenuated in smooth muscle cell-specific AT2-overexpressing mice (smAT2-Tg) compared with wild-type and AT2-knockout mice (AT2KO). Similarly, mRNA levels of relevant osteogenic and vascular smooth muscle cell marker genes were unchanged in smAT2-Tg mice, while their expression was significantly altered in wild-type mice in response to high dietary phosphate. Ex vivo, sections of thoracic aorta were cultured in media supplemented with inorganic phosphate. Aortic rings from smAT2-Tg mice showed less vascular calcification compared with those from wild-type mice. In vitro, calcium deposition induced by high-phosphate media was markedly attenuated in primary vascular smooth muscle cells derived from smAT2-Tg mice compared with the two other mouse groups. To assess the underlying mechanism, we investigated the effect of PPAR-γ, which we previously reported as one of the possible downstream effectors of AT2 stimulation. Treatment with a PPAR-γ antagonist attenuated the inhibitory effects on vascular calcification observed in smAT2-Tg mice fed an adenine and high-phosphate diet. Our results suggest that AT2 activation represents an endogenous protective pathway against vascular calcification. Its stimulation may efficiently reduce adverse cardiovascular events in patients with chronic kidney disease.
Suppression of Resting Metabolism by the Angiotensin AT<inf>2</inf> Receptor
2016, Cell Reports
Citation Excerpt :
Upon atrial natriuretic peptide (ANP) or brain natriuretic peptide (BNP) binding to the signaling receptor, NPR-A, intracellular cGMP is produced. cGMP levels have been shown to be altered by AT2 in other cell types (Bottari et al., 1992), raising the possibility that adipose natriuretic peptide signaling may be modulated by AT2 signaling. Furthermore, chronic hypertension (as previously documented in sRA mice [Grobe et al., 2010; Littlejohn et al., 2013; Sakai et al., 2007]) has been correlated with increased levels of ANP (Sagnella et al., 1986) and BNP (Kohno et al., 1992).
Activation of the brain renin-angiotensin system (RAS) stimulates energy expenditure through increasing of the resting metabolic rate (RMR), and this effect requires simultaneous suppression of the circulating and/or adipose RAS. To identify the mechanism by which the peripheral RAS opposes RMR control by the brain RAS, we examined mice with transgenic activation of the brain RAS (sRA mice). sRA mice exhibit increased RMR through increased energy flux in the inguinal adipose tissue, and this effect is attenuated by angiotensin II type 2 receptor (AT₂) activation. AT₂ activation in inguinal adipocytes opposes norepinephrine-induced uncoupling protein-1 (UCP1) production and aspects of cellular respiration, but not lipolysis. AT₂ activation also opposes inguinal adipocyte function and differentiation responses to epidermal growth factor (EGF). These results highlight a major, multifaceted role for AT₂ within inguinal adipocytes in the control of RMR. The AT₂ receptor may therefore contribute to body fat distribution and adipose depot-specific effects upon cardio-metabolic health.
AT<inf>2</inf> Receptor Signaling: Solved and Unsolved
2015, The Protective Arm of the Renin Angiotensin System (RAS): Functional Aspects and Therapeutic Implications
This chapter summarizes the current knowledge regarding the signaling pathways and biological responses linked to AT₂ receptor (AT₂R) and highlights some unsolved issues. The availability of novel nonpeptidic and highly selective AT₂R agonists should facilitate the resolution of those questions and thereby contribute to a more complete understanding of the renin–angiotensin system.
Indeed, ever since the discovery of the first signaling cascades triggered by the AT₂R, the renin–angiotensin system has revealed itself as being much more complex than initially thought. From a mere regulator of blood pressure and hydroelectrolytic homeostasis, it now appears to play a key role in such unsuspected events as development, tissue remodeling, inflammation, diabetes, neuroprotection, and even cognition.
There is no doubt that the emerging understanding of receptor heterodimerization processes as well as of their modulation by natural and synthetic ligands will soon throw some novel light on the complexity of the renin–angiotensin system.
The AT2 Receptor: Historical Perspective
2015, The Protective Arm of the Renin Angiotensin System (RAS): Functional Aspects and Therapeutic Implications
The existence of different binding sites for angiotensin II (Ang II) was postulated for years, but up to the early 1980s, the tools were not available to demonstrate it. Peptidic and nonpeptidic structures were subsequently developed and these helped three independent groups to arrive at the discovery of the two main angiotensin receptors at about the same time. There was some confusion regarding the nomenclature until the AHA Council for High Blood Pressure Research established a nomenclature committee in 1990, which proposed the names AT₁ and AT₂. The selective AT₂ receptor ligands CGP 42112 and PD 123177 and the AT₁ receptor ligand DuP 753 were the first tools to study these receptors. It rapidly became apparent that a balance exists between the two receptors, which seem to be mutually antagonistic. Although the role of the AT₁ receptor is well understood, there is still a lot of ambiguity regarding the AT₂ receptor. The peptidic nature of CGP 42112 limits its use and the development of a nonpeptidic AT₂ agonist like C21 is a clear requirement to understand the pathophysiological role of this receptor and its clinical interest.
The Angiotensin AT<inf>2</inf> Receptor: From Enigma to Therapeutic Target
2015, The Protective Arm of the Renin Angiotensin System (RAS): Functional Aspects and Therapeutic Implications
Since its discovery, 25 years ago, the angiotensin AT₂ receptor (AT₂R) has puzzled the scientific community because of its distinct localization, regulation, signaling pathways, and biological effects separating it clearly from the classical features of the renin–angiotensin system (RAS) mediated by the angiotensin AT₁ receptor. Intensive research over the years has revealed major characteristics of the AT₂R as a modulatory player involved in antiproliferation, anti-inflammation, natriuresis, neuroregeneration, and apoptosis, that is, biological programs that can counterbalance pathological processes and enable recovery from disease. The AT₂R has thus mutated from an “enigmatic” receptor to a significant member of the “protective arm” of the RAS. The recent development of novel, small molecule- and peptide-derived AT₂R agonists offers a therapeutic potential in humans with a variety of clinical indications.
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The angiotensin AT2 receptor stimulates protein tyrosine phosphatase activity and mediates inhibition of particulate guanylate cyclase

Abstract

Biochem. Biophys. Res. Commun

Biochem. Biophys. Res. Commun

J. Biol. Chem

Eur. J. Pharmacol. Mol. Pharmacol. Sect

Biochem. Biophys. Res. Commun

Biochem. Biophys. Res. Commun

Trends Biochem. Sci

FEBS Lett

Mol. Pharmacol

Nature

Nature

J. Biol. Chem

The angiotensin AT₂ receptor stimulates protein tyrosine phosphatase activity and mediates inhibition of particulate guanylate cyclase