ACE2 in the renin–angiotensin system

Verano‐Braga, Thiago; Martins, Ana Luiza Valle; Motta‐Santos, Daisy; Campagnole‐Santos, Maria José; Santos, Robson Augusto Souza

doi:10.1042/cs20200478

Cited by 45 publications

(37 citation statements)

References 129 publications

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“…Alternatively, Ang 1-7 can be generated by a preliminary cleavage of the decapeptide Ang I with the formation of Ang 1-9, followed by the removal of two additional amino acids by ACE. Ang 1-7 may also be formed directly from Ang I, following proteolytic cleavage by neprilysin, and other endopeptidases [3,22,23].…”

Section: The Ras: Counteracting Harmful and Protective Pathwaysmentioning

confidence: 99%

“…As opposed to the hazardous consequences of Ang II/AT1R stimulation, both AT2R, activated by Ang II, and MasR, triggered and internalized by Ang-(1-7) [24], exert cGMPand NO-mediated vasodilation, diuresis and natriuresis (with the induction of natriuretic peptide [25]), and attenuate inflammation, oxidative stress, cell proliferation, apoptosis, and coagulation [3,7,22,26] (Figure 1). Furthermore, Patel et al, studying obese Zucker rats, found that MasR co-localizes with AT2R in proximal tubular cells, and that both are functionally interdependent in terms of stimulating NO and promoting diuretic/natriuretic responses [27].…”

Section: Figurementioning

confidence: 99%

“…The exogenous administration of Ang-(1-7) is also an option and it is especially appealing in patients with severe COVID-19 disease, given the high incidence of AKI [95] in this ACE2-depleted disorder [4,5], and such clinical trials are currently under way [22,96]. As the bioavailability of ACE2 and of its downstream product Ang-(1-7) is low, novel compounds were developed in order to provide an extended action of Ang-(1-7), including ACE2 activators, MasR agonists, and stable Ang-(1-7) formulations [97].…”

Section: Activating Renal Ace2/ang-(1-7)/asr: Plausible Therapeutic Interventions In Renal Diseasesmentioning

confidence: 99%

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Angiotensin-(1-7)—A Potential Remedy for AKI: Insights Derived from the COVID-19 Pandemic

Heyman¹,

Walther

Abassi

2021

JCM

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Membrane-bound angiotensin converting enzyme (ACE) 2 serves as a receptor for the Sars-CoV-2 spike protein, permitting viral attachment to target host cells. The COVID-19 pandemic brought into light ACE2, its principal product angiotensin (Ang) 1-7, and the G protein-coupled receptor for the heptapeptide (MasR), which together form a still under-recognized arm of the renin–angiotensin system (RAS). This axis counteracts vasoconstriction, inflammation and fibrosis, generated by the more familiar deleterious arm of RAS, including ACE, Ang II and the ang II type 1 receptor (AT1R). The COVID-19 disease is characterized by the depletion of ACE2 and Ang-(1-7), conceivably playing a central role in the devastating cytokine storm that characterizes this disorder. ACE2 repletion and the administration of Ang-(1-7) constitute the therapeutic options currently tested in the management of severe COVID-19 disease cases. Based on their beneficial effects, both ACE2 and Ang-(1-7) have also been suggested to slow the progression of experimental diabetic and hypertensive chronic kidney disease (CKD). Herein, we report a further step undertaken recently, utilizing this type of intervention in the management of evolving acute kidney injury (AKI), with the expectation of renal vasodilation and the attenuation of oxidative stress, inflammation, renal parenchymal damage and subsequent fibrosis. Most outcomes indicate that triggering the ACE2/Ang-(1-7)/MasR axis may be renoprotective in the setup of AKI. Yet, there is contradicting evidence that under certain conditions it may accelerate renal damage in CKD and AKI. The nature of these conflicting outcomes requires further elucidation.

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Section: The Ras: Counteracting Harmful and Protective Pathwaysmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Activating Renal Ace2/ang-(1-7)/asr: Plausible Therapeutic Interventions In Renal Diseasesmentioning

confidence: 99%

See 1 more Smart Citation

Angiotensin-(1-7)—A Potential Remedy for AKI: Insights Derived from the COVID-19 Pandemic

Heyman¹,

Walther

Abassi

2021

JCM

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“…ACE2 in the renin-angiotensin system (RAS) and the apelin system, respectively [16,17]. The modulations of the cardiovascular peptide hormone systems have profound effects on physiology and pathophysiology in several organs.…”

Section: Figure 1 Structure Of Human Ace2mentioning

confidence: 99%

ACE2, a multifunctional protein – from cardiovascular regulation to COVID-19

2020

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“…One problem inherent in such re-assessment of the fragments is the choice of the peptides to study. BK-(1-9) is a substrate for carboxypeptidases (e.g., ACE and ACE2), aminopeptidases (e.g., aminopeptidase P) and endopeptidases (e.g., neutral endopeptidase, now neprilysin), thus generating many different cleavage products (Campbell, 2013;Verano-Braga et al , 2020). A general conclusion of BK-(1-9) metabolism is that its major proteolytic fragment is the BK-(1-8), which is acknowledged as the only biologically active BK peptide known to date, together with BK-(1-7) and BK-(1-5) that are regarded as biologically inert fragments (Kopylov et al , 2016;Semis et al , 2019).…”

Section: Introductionmentioning

confidence: 99%

Peptide fragments of bradykinin show unexpected biological activity not mediated by B1 or B2 receptors

Souza-Silva

Paula

Bolais-Ramos

et al. 2021

Preprint

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Background and purpose: Bradykinin [BK-(1-9)] is an endogenous nonapeptide involved in multiple physiological and pathological processes. A long-held belief is that peptide fragments of BK-(1-9) are biologically inactive. Here, we have tested the biological activities of BK-(1-9) and two major peptide fragments in human and animal systems. Experimental Approach: Levels of BK peptides in male Wistar rat plasma were quantified by mass spectrometric methods. Nitric oxide was quantified in human, mouse and rat cells, and loaded with DAF-FM. We used aortic rings from adult male Wistar rats to test vascular reactivity. Changes in blood pressure and heart rate were measured in conscious adult male Wistar rats. Key results: Plasma levels of BK-(1-7) and BK-(1-5) in rats were increased following infusion of BK-(1-9). All tested peptides induced NO production in all cell types tested. However, unlike BK-(1-9), NO production elicited by BK-(1-7) or BK-(1-5) was not inhibited by B or B receptor antagonists. BK-(1-7) or BK-(1-5) also induced concentration-dependent vasorelaxation of aortic rings, without involving B or B receptors. In vivo, either intravenous or intra-arterial administration of BK-(1-7) or BK-(1-5) induced similar hypotension response. Conclusions and implications: BK-(1-7) and BK-(1-5) are endogenous peptides present in plasma. They are formed, at least partially, through the BK-(1-9) proteolysis. BK-related peptide fragments show biological activity, not mediated by B or B receptors. These BK-fragments could constitute new, active components of the kallikrein-kinin system.

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ACE2 in the renin–angiotensin system

Cited by 45 publications

References 129 publications

Angiotensin-(1-7)—A Potential Remedy for AKI: Insights Derived from the COVID-19 Pandemic

Angiotensin-(1-7)—A Potential Remedy for AKI: Insights Derived from the COVID-19 Pandemic

ACE2, a multifunctional protein – from cardiovascular regulation to COVID-19

Peptide fragments of bradykinin show unexpected biological activity not mediated by B1 or B2 receptors

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