Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

Santos, Robson A.S.; Ferreira, Anderson J.; Verano‐Braga, Thiago; Bäder, Michael

doi:10.1530/joe-12-0341

Cited by 439 publications

(391 citation statements)

References 199 publications

(207 reference statements)

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“…Other mechanisms that contribute to the therapeutic effects of ACE inhibitors and ARBs include increased bradykinin, angiotensin II, and angiotensin-(1-7) levels and increased activation of B 2 , AT 2 , and Mas receptors. [46][47][48][49] However, when given in combination with ACE inhibitors and ARBs, the renin inhibitor aliskiren may attenuate angiotensin II and angiotensin-(1-7) levels and thus Valsartan blocks the AT 1 receptor, PD123319 blocks the AT 2 receptor, and icatibant blocks the B 2 receptor. By blocking the tonic Ang II-mediated inhibition of renin secretion, valsartan increases renin, Ang I, and Ang II levels.…”

Section: Discussionmentioning

confidence: 99%

Aliskiren Reduces Myocardial Ischemia–Reperfusion Injury by a Bradykinin B ₂ Receptor– and Angiotensin AT ₂ Receptor–Mediated Mechanism

2014

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Abstract-Angiotensin-converting enzyme inhibitors and angiotensin AT 1 receptor blockers reduce myocardial ischemiareperfusion injury via bradykinin B 2 receptor-and angiotensin AT 2 receptor-mediated mechanisms. The renin inhibitor aliskiren increases cardiac tissue kallikrein and bradykinin levels. In the present study, we investigated the effect of aliskiren on myocardial ischemia-reperfusion injury and the roles of B 2 and AT 2 receptors in this effect. Female SpragueDawley rats were treated with aliskiren (10 mg/kg per day) and valsartan (30 mg/kg per day), alone or in combination, together with the B 2 receptor antagonist icatibant (0.5 mg/kg per day) or the AT 2 receptor antagonist PD123319 (30 mg/ kg per day), for 4 weeks before myocardial ischemia-reperfusion injury. Aliskiren increased cardiac bradykinin levels and attenuated valsartan-induced increases in plasma angiotensin II levels. In vehicle-treated rats, myocardial infarct size (% area at risk, mean±SEM, n=7-13) was 43±3%. This was reduced to a similar extent by aliskiren, valsartan, and their combination to 24±3%, 25±3%, and 22±2%, respectively. Icatibant reversed the cardioprotective effects of aliskiren and the combination of aliskiren plus valsartan, but not valsartan alone, indicating that valsartan-induced cardioprotection was not mediated by the B 2 receptor. PD123319 reversed the cardioprotective effects of aliskiren, valsartan, and the combination of aliskiren plus valsartan. Aliskiren protects the heart from myocardial ischemia-reperfusion injury via a B 2 receptor-and AT 2 receptor-mediated mechanism, whereas cardioprotection by valsartan is mediated via the AT 2 receptor. In addition, aliskiren attenuates valsartan-induced increases in angiotensin II levels, thus preventing AT 2 receptor-mediated cardioprotection by valsartan. MethodsDetailed methods are provided in the online-only Data Supplement. Results Effects of Drug Treatment on Systolic BloodPressure, Body Weight, Heart Weight/Body Weight Ratio, and Mean Arterial Blood Pressure During I/R Injury Systolic blood pressure (SBP) of the 12 groups of rats during the 4-week treatment period before I/R injury is shown in the Table. In the present study, we used doses of aliskiren (10 mg/kg per day SC) and valsartan (30 mg/kg per day PO) that have little effect on blood pressure in normotensive Sprague-Dawley rats. Neither aliskiren nor valsartan caused any change in SBP during the 4 weeks (Table). However, SBP in rats receiving the combination of aliskiren plus valsartan was less than that in vehicle-treated rats. In contrast, SBP in rats receiving the B 2 receptor antagonist icatibant (0.5 mg/kg per day SC) alone was higher than that of vehicle-treated rats. Rats treated with aliskiren, valsartan, and the combination of aliskiren plus valsartan had lower SBP during combined treatment with icatibant than that of rats treated with icatibant alone. Treatment with the AT 2 receptor antagonist PD123319 (30 mg/kg per day SC) alone did not affect blood pressure. During combined treatment w...

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Section: Discussionmentioning

confidence: 99%

Aliskiren Reduces Myocardial Ischemia–Reperfusion Injury by a Bradykinin B ₂ Receptor– and Angiotensin AT ₂ Receptor–Mediated Mechanism

2014

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“…Angiotensinogen is converted into biologically inactive ANG-I by the enzyme renin, which in turn is converted into biologically active ANG-II by angiotensin-converting enzyme (ACE). Although recent studies have identified additional proteins interacting with ANG-II and renin, such as prorenin, renin receptors, and ACE-2, the enzymatic reactions resulting in the synthesis of ANG-II constitute the renin-angiotensin system (RAS; Santos et al 2013). Based on in vivo and in vitro studies, ANG-II is known to increase the expression and/or activities of all major transporters involved with Na C and acid transport in the various segments of the nephron, including Na C /H C exchanger 3 (NHE3; Geibel et al 1990, Cano et al 1994), H C -ATPase (Rothenberger et al 2007), epithelial Na C channel (Peti-Peterdi et al 2002), and thiazide-sensitive Na C -Cl K cotransporter (Sandberg et al 2007, San-Cristobal et al 2009, Castaneda-Bueno et al 2012.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin-II promotes Na+ uptake in larval zebrafish, Danio rerio, in acidic and ion-poor water

Kumai

Bernier

Perry

2013

Journal of Endocrinology

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The contribution of the renin-angiotensin system (RAS) to Na C uptake was investigated in larval zebrafish (Danio rerio). At 4 days post fertilization (dpf), the level of whole-body angiotensin-II (ANG-II) was significantly increased after 1-or 3-h exposure to acidic (pHZ4.0) or ion-poor water (20-fold dilution of Ottawa tapwater), suggesting rapid activation of the RAS. Long-term (24 h) treatment of 3 dpf larvae with ANG-I or ANG-II significantly increased Na C uptake which was accompanied by an increase in mRNA expression of the NaInduction of Na C uptake by exposure to ANG-I was blocked by simultaneously treating larvae with lisinopril (an angiotensin-converting enzyme inhibitor). Acute (2 h) exposure to acidic water or ion-poor water led to significant increase in Na C uptake which was partially blocked by the ANG-II receptor antagonist, telmisartan. Consistent with these data, translational knockdown of renin prevented the stimulation of Na C uptake following exposure to acidic or ion-poor water. The lack of any effects of pharmacological inhibition (using RU486), or knockdown of glucocorticoid receptors on the stimulation of Na C uptake during acute exposure to acidic or ion-poor environments, indicates that the acute effects of RAS occur independently of cortisol signaling. The results of this study demonstrate that the RAS is involved in Na C homeostasis in larval zebrafish. Key Words" angiotensin-II" cortisol " zebrafish " osmoregulation " ion-poor water " acidic water

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“…Angiotensin-converting enzyme type 2 (ACE2), a pivotal RAS component, has been found in many regions in the bran, including SFO and PVN (8). Numerous studies have shown that ACE2 has opposite properties to that of the classic RAS via its conversion of angiotensin (ANG) II into ANG-(1-7) (20). We previously reported that overexpression of ACE2 in the brain blunts the development of hypertension in several animal models (9,31).…”

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confidence: 99%

Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress

Xia

Queiroz

Sriramula

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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-Endoplasmic reticulum (ER) stress was previously reported to contribute to neurogenic hypertension while neuronal angiotensin-converting enzyme type 2 (ACE2) overexpression blunts the disease. To assess which brain regions are important for ACE2 beneficial effects and the contribution of ER stress to neurogenic hypertension, we first used transgenic mice harboring a floxed neuronal hACE2 transgene (SL) and tested the impact of hACE2 knockdown in the subfornical organ (SFO) and paraventricular nucleus (PVN) on deoxycorticosterone acetate (DOCA)-salt hypertension. SL and nontransgenic (NT) mice underwent DOCA-salt or sham treatment while infected with an adenoassociated virus (AAV) encoding Cre recombinase (AAV-Cre) or a control virus (AAV-green fluorescent protein) to the SFO or PVN. DOCA-salt-induced hypertension was reduced in SL mice, with hACE2 overexpression in the brain. This reduction was only partially blunted by knockdown of hACE2 in the SFO or PVN, suggesting that both regions are involved but not essential for ACE2 regulation of blood pressure (BP). DOCA-salt treatment did not increase the protein levels of ER stress and autophagy markers in NT mice, despite a significant increase in BP. In addition, these markers were not affected by hACE2 overexpression in the brain, despite a significant reduction of hypertension in SL mice. To further assess the role of ER stress in neurogenic hypertension, NT mice were infused intracerebroventricularlly with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, during DOCA-salt treatment. However, TUDCA infusion failed to blunt the development of hypertension in NT mice. Our data suggest that brain ER stress does not contribute to DOCA-salt hypertension and that ACE2 blunts neurogenic hypertension independently of ER stress. neurogenic hypertension; central nervous system; blood pressure; angiotensin-converting enzyme type 2; deoxycorticosterone acetate THE BRAIN RENIN-ANGIOTENSIN system (RAS) plays a critical role in the regulation of blood pressure (BP) via its actions in various brain regions, such as subfornical organ (SFO), paraventricular nucleus (PVN), rostral ventrolateral medulla (RVLM), and nucleus tractus solitarius (NTS) (17). An overactivated brain RAS leads to the development of neurogenic hypertension at least in part by increasing sympathetic outflow, blunting the baroreflex sensitivity and stimulating vasopressin secretion (17). Angiotensin-converting enzyme type 2 (ACE2), a pivotal RAS component, has been found in many regions in the bran, including SFO and PVN (8). Numerous studies have shown that ACE2 has opposite properties to that of the classic RAS via its conversion of angiotensin (ANG) II into ANG-(1-7) (20). We previously reported that overexpression of ACE2 in the brain blunts the development of hypertension in several animal models (9, 31). However, it is not clear which brain regions might be more important for the preservation of ACE2 compensatory activity.

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Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

Cited by 439 publications

References 199 publications

Aliskiren Reduces Myocardial Ischemia–Reperfusion Injury by a Bradykinin B ₂ Receptor– and Angiotensin AT ₂ Receptor–Mediated Mechanism

Aliskiren Reduces Myocardial Ischemia–Reperfusion Injury by a Bradykinin B ₂ Receptor– and Angiotensin AT ₂ Receptor–Mediated Mechanism

Angiotensin-II promotes Na+ uptake in larval zebrafish, Danio rerio, in acidic and ion-poor water

Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress

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Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

Cited by 439 publications

References 199 publications

Aliskiren Reduces Myocardial Ischemia–Reperfusion Injury by a Bradykinin B 2 Receptor– and Angiotensin AT 2 Receptor–Mediated Mechanism

Aliskiren Reduces Myocardial Ischemia–Reperfusion Injury by a Bradykinin B 2 Receptor– and Angiotensin AT 2 Receptor–Mediated Mechanism

Angiotensin-II promotes Na+ uptake in larval zebrafish, Danio rerio, in acidic and ion-poor water

Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress

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Aliskiren Reduces Myocardial Ischemia–Reperfusion Injury by a Bradykinin B ₂ Receptor– and Angiotensin AT ₂ Receptor–Mediated Mechanism

Aliskiren Reduces Myocardial Ischemia–Reperfusion Injury by a Bradykinin B ₂ Receptor– and Angiotensin AT ₂ Receptor–Mediated Mechanism