The Angiotensin AT<sub>2</sub>Receptor: From a Binding Site to a Novel Therapeutic Target

Steckelings, Ulrike Muscha; Widdop, Robert E; Sturrock, Edward D.; Lubbe, Lizelle; Hussain, Tahir; Kaschina, Elena; Unger, Thomas; Hallberg, Anders; Carey, Robert M.; Sumners, Colin

doi:10.1124/pharmrev.120.000281

Cited by 42 publications

(59 citation statements)

References 925 publications

(1,400 reference statements)

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“…Moreover, the hydrolysate reduced blood pressure in rats by modulating the renin-angiotensin system (RAS), including reduction of angiotensin II-type 1 receptor and induction of AT2R abundance in the aorta of rats [ 10 ]. AT2R is not only involved in the modulation of blood pressure by opposing angiotensin II-type 1 receptor activity, but its stimulation is associated with reno- and cardio-protective effects, anti-inflammatory and antifibrotic action, among others as extensively reviewed elsewhere [ 37 ]. In fact, RAS modulation is linked to hepatic fibrosis in rodents and humans with NAFLD [ 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

An Egg White-Derived Peptide Enhances Systemic Insulin Sensitivity and Modulates Markers of Non-Alcoholic Fatty Liver Disease in Obese, Insulin Resistant Mice

et al. 2023

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Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, is a global health problem. Currently, no pharmacological treatment is approved for NAFLD. Natural health products, including bioactive peptides, are potential candidates to aid in the management of metabolic syndrome-related conditions, including insulin resistance and obesity. In this study, we hypothesized that an egg-white-derived bioactive peptide QAMPFRVTEQE (Peptide 2) would improve systemic and local white adipose tissue insulin sensitivity, thereby preventing high-fat diet-induced exacerbation of pathological features associated with NAFLD, such as lipid droplet size and number, inflammation, and hepatocyte hypertrophy in high-fat diet-fed mice. Similar to rosiglitazone, Peptide 2 supplementation improved systemic insulin resistance during the hyperinsulinemic-euglycemic clamp and enhanced insulin signalling in white adipose tissue, modulating ex vivo lipolysis. In the liver, compared with high-fat diet fed animals, Peptide 2 supplemented animals presented decreased hepatic cholesterol accumulation (p < 0.05) and area of individual hepatic lipid droplet by around 50% (p = 0.09) and reduced hepatic inflammatory infiltration (p < 0.05) whereas rosiglitazone exacerbated steatosis. In conclusion, Peptide 2 supplementation improved insulin sensitivity and decreased hepatic steatosis, unlike the insulin-sensitizing drug rosiglitazone.

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Section: Discussionmentioning

confidence: 99%

An Egg White-Derived Peptide Enhances Systemic Insulin Sensitivity and Modulates Markers of Non-Alcoholic Fatty Liver Disease in Obese, Insulin Resistant Mice

et al. 2023

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“…Based on the studies using the bleomycin and the monocrotaline models [ 27 , 28 ] and a recent review of the unique signaling pathways and molecular mechanisms of AT 2 R activation [ 23 ], the beneficial effects of C21 treatment are believed to be mediated by reduced levels of pro-fibrotic grow factors and proinflammatory cytokines such as TGF-β, CTGF, IL-1β, IL-6, and TNF.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, while Ang-(1-7) is considered to signal mainly via the Mas receptor [ 21 ], it is also an AT 2 R agonist at nanomolar concentrations [ 22 ]. C21 (also known as Compound 21 or buloxibutid), the first AT 2 R agonist in clinical development, is a low molecular weight, orally available, selective, high-affinity AT 2 R agonist with low affinity to a range of other receptors tested, including the AT 1 R and the Mas receptor [ 23 , 24 ]. The unique signaling pathways and molecular mechanisms of AT 2 R activation are described in a recent comprehensive review [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…C21 (also known as Compound 21 or buloxibutid), the first AT 2 R agonist in clinical development, is a low molecular weight, orally available, selective, high-affinity AT 2 R agonist with low affinity to a range of other receptors tested, including the AT 1 R and the Mas receptor [ 23 , 24 ]. The unique signaling pathways and molecular mechanisms of AT 2 R activation are described in a recent comprehensive review [ 23 ]. In a phase 2 clinical trial, C21 decreased the need for oxygen therapy in hospitalized patients with COVID-19 [ 25 ], and the compound is currently also in an idiopathic pulmonary fibrosis clinical study [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Effects of the Oral Angiotensin II Type 2 Receptor Agonist C21 in Sugen-Hypoxia Induced Pulmonary Hypertension in Rats

Tornling

Batta

Salvail³

et al. 2023

IJMS

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Substantial evidence supports the involvement of the renin-angiotensin system in pulmonary hypertension (PH), and the angiotensin II type 2 receptor (AT2R) is known to exert tissue protective actions. The effect of the selective AT2R agonist C21 (also known as Compound 21 or buloxibutid) was evaluated in the rat Sugen-hypoxia PH model. After a single injection of Sugen 5416 and hypoxia for 21 days, C21 (2 or 20 mg/kg) or vehicle was administered perorally twice daily from Day 21 to Day 55. On Day 56, hemodynamic assessments were performed, and lung and heart tissue were prepared for quantification of cardiac and vascular remodeling and fibrosis. Treatment with C21 20 mg/kg improved cardiac output and stroke volume and decreased right ventricular hypertrophy (all p < 0.05). Treatment with C21 2 mg/kg significantly decreased vessel wall and muscular layer thickness and increased the luminal opening in vessels >100 μm (all p < 0.05). There were no significant differences between the two C21 doses on any parameter, and post hoc analyses comparing the merged C21 groups with the vehicle group showed that C21 treatment reduced vascular remodeling (reduced endothelial proliferation and thickening of the vascular wall) in vessels of all sizes; moreover, the diastolic pulmonary artery pressure and right ventricular pressure were reduced along with reduction of right ventricular hypertrophy. Sugen 5416 and hypoxia increased pulmonary collagen deposition, which was counteracted by C21 20 mg/kg. In conclusion, the effects of C21 on vascular remodeling, hemodynamic alterations, and fibrosis suggest that AT2R agonists may have a role in Group 1 and 3 PH treatment.

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“…ACE2 is not entirely specific for the recognition and hydrolysis of Ang II as the metallopeptidase converts Ang I to Ang-(1–9), a ligand for the AT 2 R that also opposes the actions of the Ang II-AT 1 R axis to inhibit fibrosis and inflammation. 19 , 47 In this regard, ACE2-dependent generation of Ang-(1–9) may compensate for the loss of Ang II by ACE2 to stimulate the AT 2 R. However, human ACE2 exhibits a higher catalytic efficiency (k cat [peptidase catalytic constant]/K M [peptidase Michaelis-Menten constant], ~100-fold) for the hydrolysis of Ang II to Ang-(1–7) versus the processing of Ang I to Ang-(1–9). 48 As to other vasoactive peptides, ACE2 degrades the des-Arg 9 form of bradykinin (des-Arg 9 -BK), the ligand for the BKB1R (BK type B1 receptor) involved in the activation of proinflammatory pathways.…”

Section: Sars-cov-2 Infection and Ace2mentioning

confidence: 99%

Renin-Angiotensin System and Sex Differences in COVID-19: A Critical Assessment

Chappell

2023

Circulation Research

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The current epidemic of corona virus disease (COVID-19) has resulted in an immense health burden that became the third leading cause of death and potentially contributed to a decline in life expectancy in the United States. The severe acute respiratory syndrome-related coronavirus-2 binds to the surface-bound peptidase angiotensin-converting enzyme 2 (ACE2, EC 3.4.17.23) leading to tissue infection and viral replication. ACE2 is an important enzymatic component of the renin-angiotensin system (RAS) expressed in the lung and other organs. The peptidase regulates the levels of the peptide hormones Ang II and Ang-(1–7), which have distinct and opposing actions to one another, as well as other cardiovascular peptides. A potential consequence of severe acute respiratory syndrome-related coronavirus-2 infection is reduced ACE2 activity by internalization of the viral-ACE2 complex and subsequent activation of the RAS (higher ratio of Ang II:Ang-[1–7]) that may exacerbate the acute inflammatory events in COVID-19 patients and possibly contribute to the effects of long COVID-19. Moreover, COVID-19 patients present with an array of autoantibodies to various components of the RAS including the peptide Ang II, the enzyme ACE2, and the AT 1 AT 2 and Mas receptors. Greater disease severity is also evident in male COVID-19 patients, which may reflect underlying sex differences in the regulation of the 2 distinct functional arms of the RAS. The current review provides a critical evaluation of the evidence for an activated RAS in COVID-19 subjects and whether this system contributes to the greater severity of severe acute respiratory syndrome-related coronavirus-2 infection in males as compared with females.

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The Angiotensin AT₂Receptor: From a Binding Site to a Novel Therapeutic Target

Cited by 42 publications

References 925 publications

An Egg White-Derived Peptide Enhances Systemic Insulin Sensitivity and Modulates Markers of Non-Alcoholic Fatty Liver Disease in Obese, Insulin Resistant Mice

An Egg White-Derived Peptide Enhances Systemic Insulin Sensitivity and Modulates Markers of Non-Alcoholic Fatty Liver Disease in Obese, Insulin Resistant Mice

Effects of the Oral Angiotensin II Type 2 Receptor Agonist C21 in Sugen-Hypoxia Induced Pulmonary Hypertension in Rats

Renin-Angiotensin System and Sex Differences in COVID-19: A Critical Assessment

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The Angiotensin AT2Receptor: From a Binding Site to a Novel Therapeutic Target

Cited by 42 publications

References 925 publications

An Egg White-Derived Peptide Enhances Systemic Insulin Sensitivity and Modulates Markers of Non-Alcoholic Fatty Liver Disease in Obese, Insulin Resistant Mice

An Egg White-Derived Peptide Enhances Systemic Insulin Sensitivity and Modulates Markers of Non-Alcoholic Fatty Liver Disease in Obese, Insulin Resistant Mice

Effects of the Oral Angiotensin II Type 2 Receptor Agonist C21 in Sugen-Hypoxia Induced Pulmonary Hypertension in Rats

Renin-Angiotensin System and Sex Differences in COVID-19: A Critical Assessment

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Resources

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The Angiotensin AT₂Receptor: From a Binding Site to a Novel Therapeutic Target