The ANG-(1–7)/ACE2/mas axis in the regulation of nephron function

Ferrario, Carlos M.; Varagić, Jasmina

doi:10.1152/ajprenal.00110.2010

Cited by 135 publications

(149 citation statements)

References 159 publications

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“…The data in that study also showed that the biphasic effect of ANG-(1-7) on the Na+/H+ exchanger occurred via the Mas receptor and that A779 (a Mas receptor antagonist) abolished this hormonal biphasic effect. These results are also consistent with previously described findings in the literature that indicated that the renal effects of ANG-(1-7) are dose dependent and mediated, at least in part, by the Mas receptor [193][194][195][196]. Nevertheless, in isolated rat proximal straight tubules (S3 segment), it was shown that, like ANG II, ANG-(1-7) exerts a biphasic effect through AT1 receptors: at physiological levels, ANG-(1-7) increases fluid and bicarbonate reabsorption, while at high concentrations, ANG-(1-7) decreases these parameters [183].…”

Section: Actions Of Ang-(1-7) In the Kidneysupporting

confidence: 93%

“…Therefore, these results indicate that in hypertensive animals, a high plasma concentration of ANG-(1-7) [126, 189,190] attenuates hypertension. Figure 3 shows that proximal convoluted tubules in SHR rats exhibited a mean baseline [Ca 2+ ]i of 96 ± 2 nM [195], and the subsequent addition of ANG-(1-7) (10 -9 or 10 -6 M) increased it (by approximately 30% and 63%, respectively). The biphasic effects of ANG-(1-7) on the Na+/H + exchanger in Wistar, SHR (hypertensives) and controls WKY (normotensives) rats are summarized in Figure 6.…”

Section: Actions Of Ang-(1-7) In the Kidneymentioning

confidence: 99%

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ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

Mello-Aires¹,

Dellova²,

Castelo‐Branco³

et al. 2017

Nephrol Renal Dis

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This article reviews the main body of knowledge regarding NHE1 and NHE3 exchangers and their interaction with Angiotensin II, Angiotensin-(1-7), Aldosterone and Arginine Vasopressin, particularly their renal actions. This work addresses the biphasic effects of different hormonal doses on NHE1 or NHE3 in proximal tubule in Wistar, SHR (hypertensives) and their control WKY (normotensives) rats or MDCK cells (which share similarities with the collecting duct). The hormones were applied alone, with their inhibitors or plus agents that change the [Ca 2+ ]i. The data are compatible with hormonal stimulation of these exchangers by increases of [Ca 2+ ]i in lower range, and inhibition at high [Ca 2+ ]i. In MDCK cells and Wistar rats, low doses of ANG II, ALDO or AVP stimulated the exchangers, while high doses inhibited them. ANG-(1-7), in Wistar or WKY rats has inverse, dose-dependent effects. In SHR rats, the biphasic effects of ANG-(1-7) were similar to the effects of ANG II, ALDO or AVP in Wistar rats. The interactions between these effects may represent a mechanism that regulates extracellular volume. In hypertensives animals, a high plasma level of ANG-(1-7) inhibited NHE3 in the proximal tubule, which mitigated hypertension. Figure 6 shows a schematic model to describe these biphasic hormonal effects.

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Section: Actions Of Ang-(1-7) In the Kidneysupporting

confidence: 93%

Section: Actions Of Ang-(1-7) In the Kidneymentioning

confidence: 99%

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

Mello-Aires¹,

Dellova²,

Castelo‐Branco³

et al. 2017

Nephrol Renal Dis

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“…The potential impact of removing kidney ACE on local ACE2 expression and Ang-(1-7) production is excluded from our analysis. In many instances, the renal actions of Ang-(1-7) counteract those of Ang II (40). Therefore, the possibility exists that some of the protection observed in the mutant mice is due to the unopposed actions of the Ang-(1-7)/ Mas receptor axis.…”

Section: Figurementioning

confidence: 99%

The absence of intrarenal ACE protects against hypertension

González-Villalobos

Janjoulia²,

Fletcher³

et al. 2013

J. Clin. Invest.

177

210

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Activation of the intrarenal renin-angiotensin system (RAS) can elicit hypertension independently from the systemic RAS. However, the precise mechanisms by which intrarenal Ang II increases blood pressure have never been identified. To this end, we studied the responses of mice specifically lacking kidney angiotensin-converting enzyme (ACE) to experimental hypertension. Here, we show that the absence of kidney ACE substantially blunts the hypertension induced by Ang II infusion (a model of high serum Ang II) or by nitric oxide synthesis inhibition (a model of low serum Ang II). Moreover, the renal responses to high serum Ang II observed in wild-type mice, including intrarenal Ang II accumulation, sodium and water retention, and activation of ion transporters in the loop of Henle (NKCC2) and distal nephron (NCC, ENaC, and pendrin) as well as the transporter activating kinases SPAK and OSR1, were effectively prevented in mice that lack kidney ACE. These findings demonstrate that ACE metabolism plays a fundamental role in the responses of the kidney to hypertensive stimuli. In particular, renal ACE activity is required to increase local Ang II, to stimulate sodium transport in loop of Henle and the distal nephron, and to induce hypertension. IntroductionHypertension affects more than 1.5 billion people worldwide and is a key contributor to stroke and cardiovascular and kidney disease. The importance of the renin-angiotensin system (RAS) in the origins of this disorder is underscored by the blood pressure-lowering effects of angiotensin-converting enzyme (ACE) inhibitors and Ang II receptor blockers. However, plasma renin activity, the clinical index used to determine systemic RAS status, is distributed over a wide range in hypertensive subjects (1, 2). This observation prompts the suggestion that alterations in tissue-specific RAS, not detected by plasma renin activity, may underlie hypertension. The kidneys play a central role in long-term blood pressure control through their regulation of sodium and fluid balance. Because renal salt retention is strongly influenced by Ang II and there is a complete RAS along the nephron, it has been suggested that increased local Ang II formation may induce hypertension. Indeed, using gene-targeted mice, we and others have shown that increased intrarenal Ang II formation results in hypertension (3-6). As a whole, these observations suggest that renal Ang II synthesis has important consequences for nephron function and the development of hypertension. However, precisely how the intrarenal generation of Ang II elevates blood pressure is not known. Therefore, we tested the hypothesis that, in conditions in which the intrarenal RAS becomes activated, local Ang II synthesis enhances sodium and water reabsorption along the nephron. In addition, we postulated that inhibiting intrarenal Ang II formation effectively protects against hypertension.

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“…In this way, ACE2/Ang-(1-7)/Mas axis can counteract most of the deleterious effects of ACE/Ang Ⅱ/AT1. It has been corroborated that acute intravenous infusion of Ang-(1-7) induces diuresis, natriuresis and renal vasodilatation [50] . Like to Ang-(1-7), there is another heptapeptide derived from Ang Ⅱ having the opposite effect to Ang Ⅱ, namely Ang-(2-8), also known as Ang Ⅲ. Ang Ⅱ can be hydrolyzed by aminopeptidase A, generating Ang Ⅲ [51] ( Figure 1).…”

Section: New Members Of Ras: Ang Ii-derived Peptidesmentioning

confidence: 85%

Renin-angiotensin system in the kidney: What is new?

Ferrão

Lara

Lowe

2014

WJN

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The renin-angiotensin system (RAS) has been known for more than a century as a cascade that regulates body fluid balance and blood pressure. Angiotensin Ⅱ (Ang Ⅱ) has many functions in different tissues; however it is on the kidney that this peptide exerts its main functions. New enzymes, alternative routes for Ang Ⅱ formation or even active Ang Ⅱ-derived peptides have now been described acting on Ang Ⅱ AT1 or AT2 receptors, or in receptors which have recently been cloned, such as Mas and AT4. Another interesting observation was that old members of the RAS, such as angiotensin converting enzyme (ACE), renin and prorenin, well known by its enzymatic activity, can also activate intracellular signaling pathways, acting as an outside-in signal transduction molecule or on the renin/(Pro)renin receptor. Moreover, the endocrine RAS, now is also known to have paracrine, autocrine and intracrine action on different tissues, expressing necessary components for local Ang Ⅱ formation. This in situ formation, especially in the kidney, increases Ang Ⅱ levels to regulate blood pressure and renal functions. These discoveries, such as the ACE2/Ang-(1-7)/Mas axis and its antangonistic effect rather than classical deleterious Ang Ⅱ effects, improves the development of new drugs for treating hypertension and cardiovascular diseases. Key words: Renin-angiotensin system; Angiotensin Ⅱ; Kidney; Hypertension treatment; Receptor Core tip: Activation of the angiotensin converting enzyme (ACE)/ Angiotensin Ⅱ (Ang Ⅱ)/AT1 axis leads to vasoconstriction, anti-diuresis, anti-natriuresis, release of aldosterone and anti-diuretic hormone, which can result in hypertension, renal and cardiovascular diseases. Inhibition of renin and ACE or blocking AT1 receptor is the most used therapies for heart failure and hypertension. Nevertheless, the discovery of local Ang Ⅱ synthesis, new Ang Ⅱ metabolites, receptors and axis of this system, makes possible the development of new drugs and strategies for renal and cardiovascular diseases treatment, such as activation of ACE2/Ang-(1-7)/ Mas axis, which presents opposite effects of AT1 activation by Ang Ⅱ.

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The ANG-(1–7)/ACE2/mas axis in the regulation of nephron function

Cited by 135 publications

References 159 publications

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

The absence of intrarenal ACE protects against hypertension

Renin-angiotensin system in the kidney: What is new?

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