Opposing Actions of Angiotensin-(1-7) and Angiotensin II in the Brain of Transgenic Hypertensive Rats

Moriguchi, Atsushi; Tallant, E. Ann; Matsumura, Kiyoshi; Reilly, Thomas M.; Walton, Harry L.; Ganten, Detlev; Ferrario, Carlos M.

doi:10.1161/01.hyp.25.6.1260

Cited by 81 publications

(55 citation statements)

References 38 publications

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“…Similar to the periphery, many of the responses to ANG-(1-7) in the central nervous system oppose those of ANG II. Moriguchi et al (29) showed that intracerebroventricular administration of an ANG II antibody lowered blood pressure in [mRen-2]27 transgenic hypertensive rats; conversely, an antibody that selectively bound ANG-(1-7) raised pressure. In the dorsal medulla oblongata, ANG II attenuated baroreceptor reflex control of heart rate, whereas ANG-(1-7) augmented the reflex, suggesting that the balance of the two peptides sets the sensitivity of the baroreflex.…”

Section: Discussionmentioning

confidence: 99%

Distinct roles for ANG II and ANG-(1–7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes

Gallagher¹,

Chappell²,

Ferrario³

et al. 2006

American Journal of Physiology-Cell Physiology

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168

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. Distinct roles for ANG II and ANG-(1-7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes. Am J Physiol Cell Physiol 290: C420 -C426, 2006. First published September 21, 2005; doi:10.1152/ajpcell.00409.2004.-Angiotensin-converting enzyme 2 (ACE2) is a homolog of ACE that preferentially forms angiotensin-(1-7) [ANG-(1-7)] from angiotensin II (ANG II). Incubation of neonatal rat cerebellar or medullary astrocytes with ANG II reduced ACE2 mRNA by ϳ60%, suggesting transcriptional regulation of the enzyme. In contrast, ANG II had no effect on ACE mRNA in astrocytes isolated from either brain region, demonstrating a differential regulation of the two enzymes by ANG II. The ANG II-mediated reduction in ACE2 mRNA was blocked by the angiotensin type 1 (AT1) receptor antagonists losartan or valsartan; the angiotensin type 2 (AT 2) antagonist PD123319 was ineffective. The reduction in ACE2 mRNA by ANG II also was associated with a 50% decrease in cerebellar and medullary ACE2 protein, which was blocked by losartan. Treatment of medullary astrocytes with ANG-(1-7), the product of ACE2 hydrolysis of ANG II, did not affect ACE2 mRNA; however, ANG-(1-7) prevented the ANG II-mediated reduction in ACE2 mRNA. The addition of ]-ANG-(1-7), a selective AT (1-7) receptor antagonist, blocked the inhibitory actions of ANG-(1-7). These data are the first to demonstrate transcriptional regulation of ACE2 by ANG II and ANG-(1-7). Because ACE2 preferentially converts ANG II to ANG-(1-7), downregulation of the enzyme by ANG II constitutes a novel positive feed-forward system within the brain that may favor ANG II-mediated neural responses. Furthermore, the modulatory role of ANG-(1-7) in the transcriptional regulation of ACE2 by ANG II suggests a complex interplay between these peptides that is mediated by distinct receptor systems. central nervous system; glia; angiotensin receptor THE RENIN-ANGIOTENSIN SYSTEM is a primary regulator of blood pressure, homeostasis, and cell growth. The major bioactive components of the renin-angiotensin system are produced from the conversion of the precursor angiotensinogen to the decapeptide angiotensin I (ANG I). The cascade diverges with the processing of ANG I to the peptide hormones, ANG II and ANG-(1-7), products with different carboxy termini and contrasting biological actions mediated by distinct high-affinity membrane receptors. ANG II acts through two pharmacological classes of G protein-coupled receptors, AT 1 and AT 2 receptors (4, 8), whereas the G protein-coupled receptor mas was recently identified as a functional ANG-(1-7) receptor (37,44,46). In addition to the classic endocrine system, the reninangiotensin system is active within tissues, resulting in the local synthesis, release, and action of angiotensin peptides (1, 6, 11).Angiotensin-converting enzyme 2 (ACE2) is a newly identified component of the renin-angiotensin system that catalyzes the conversion of ANG I to ANG-(1-9) (48, 50, 52). More important, ACE2 converts the vasoconstrictor and growth promoter ANG ...

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Section: Discussionmentioning

confidence: 99%

Distinct roles for ANG II and ANG-(1–7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes

Gallagher¹,

Chappell²,

Ferrario³

et al. 2006

American Journal of Physiology-Cell Physiology

Self Cite

168

121

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“…Ang-(1-7) antibody purification and characterization have been described previously. 15 The secondary antibody used was biotinylated goat anti-rabbit for Ang-(1-7) staining or biotinylated horse anti-mouse for ACE2 staining (Vector Laboratories), diluted 1:400 in 1% BSA. Sections were stained brown with 3,3Ј-diaminobenzidine (DAB, Sigma Chemical Co) in Tris-buffered saline (0.05 mol/L, pH 7.6 to 7.7) and counterstained with hematoxylin before being dehydrated and mounted.…”

Section: Immunocytochemistrymentioning

confidence: 99%

Enhanced Renal Immunocytochemical Expression of ANG-(1-7) and ACE2 During Pregnancy

et al. 2003

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Abstract-Previously we demonstrated that kidney concentration and urinary excretion of angiotensin-(1-7) are increased during normal pregnancy in rats. Since this finding may reflect local kidney production of angiotensin-(1-7), we determined the immunocytochemical distribution of angiotensin-(1-7) and its newly described processing enzyme, ACE2, in kidneys of virgin and 19-day-pregnant Sprague-Dawley rats. Sprague-Dawley rats were killed at the 19th day of pregnancy, and tissues were prepared for immunocytochemical by using a polyclonal antibody to angiotensin-(1-7) or a monoclonal antibody to ACE2. Angiotensin-(1-7) immunostaining was predominantly localized to the renal tubules traversing both the inner cortex and outer medulla. ACE2 immunostaining was localized throughout the cortex and outer medulla and was visualized in the renal tubules of both virgin and pregnant rats. The quantification of angiotensin-(1-7) and ACE2 immunocytochemical staining showed that in pregnant animals, the intensity of the staining increased by 56% and 117%, respectively (PϽ0.05). This first demonstration of the immunocytochemical distribution of angiotensin-(1-7) and ACE2 in kidneys of pregnant rats shows that pregnancy increases angiotensin-(1-7) immunocytochemical expression in association with increased ACE2 intensity of staining. The findings suggest that ACE2 may contribute to the local production and overexpression of angiotensin-(1-7) in the kidney during pregnancy. Key Words: angiotensin Ⅲ renin-angiotensin system Ⅲ pregnancy Ⅲ kidney Ⅲ angiotensin-converting enzyme 2 P reviously we demonstrated for the first time that activation of the renin-angiotensin system (RAS) during pregnancy is associated with augmented kidney concentration and urinary excretion of angiotensin-(1-7) [Ang-(1-7)]. 1 Ang-(1-7), formed from either Ang I or Ang II and shown to exert vasodilatory, antiproliferative and natriuretic effects, 1-9 was the predominate angiotensin peptide found in the kidney and urine of pregnant rats, reaching levels that were 3-and 2.5-fold greater than Ang II in the kidney and urine, respectively. There was an increase in the Ang-(1-7)/Ang II, indicating that there may be increased enzymatic conversion of Ang II into Ang-(1-7). At the same time, there was no change in Ang-(1-7) in the circulation. These findings suggest that there may be an enhanced renal local production and overexpression of Ang-(1-7) in pregnancy without a systemic contribution.The profile of peptides in the kidney with increased content of Ang-(1-7) without a buildup in the levels of Ang II is consistent with an enzymatic pathway of a recently described enzyme of the RAS, ACE2. ACE2 is a carboxypeptidase that converts Ang I into Ang-(1-9), but it also exhibits high catalytic efficiency to generate Ang-(1-7) from Ang II. 10 -12 The ACE2 catalytic activity for Ang II as compared with Ang I is 400-fold higher, making Ang II a central player in the metabolic pathway for the formation of Ang-(1-7). Chappell et al 13 provided the first direct evidence f...

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“…The Ang-(1-7) antibody was purified and characterized by us as described elsewhere. 15 The next day, tissues were washed with PBS and incubated for 3 hours at 4°C with a biotinylated anti-rabbit antibody at a dilution of 1:400 in 1% BSA. Slides were rinsed with PBS, blotted dry, and reacted immunocytochemically by the avidinbiotin method (Vector Laboratories) 16 and stained brown with 3,3Ј-diaminobenzidine (Sigma Chemical Co) in Tris buffered saline (0.05 mol/L, pH 7.6 to 7.7).…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

Cardiac Angiotensin-(1-7) in Ischemic Cardiomyopathy

et al. 2003

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Background-Accumulating evidence suggests that angiotensin-(1-7) (Ang- [1][2][3][4][5][6][7]) may play an important role in counteracting the pressor, proliferative, and profibrotic actions of angiotensin II in the heart. Thus, we evaluated whether Ang-(1-7) is expressed in the myocardium of normal rats and those in which myocardial infarction was produced 4 weeks beforehand. Methods and Results-The left coronary artery in 10-week-old Lewis rats was either ligated (nϭ5) or exposed but not occluded in age-matched controls (sham; nϭ5). Left ventricular end-diastolic pressures were significantly elevated 4 weeks after myocardial infarction (25Ϯ1 versus 5Ϯ1 mm Hg for sham; PϽ0.001), whereas left ventricular systolic pressures were significantly reduced (ligated 86Ϯ4 versus sham 110Ϯ5 mm Hg; PϽ0.01). Hemodynamic effects of coronary artery ligation were accompanied by significant cardiac hypertrophy (heart weight to body weight: ligated 4.3Ϯ0.1 versus sham 2.9Ϯ0.1 mg/g; PϽ0.001). In both ligated and sham rats, Ang-(1-7) immunoreactivity was limited to cardiac myocytes and absent in interstitial cells and coronary vessels. Ang-(1-7) immunoreactivity was significantly augmented in ventricular tissue surrounding the infarct area in the heart of rats with myocardial infarction. Conclusions-Development of heart failure subsequent to coronary artery ligation leads to increased expression of Ang-(1-7),which was restricted to myocytes. (Circulation. 2003;108:2141-2146.)

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Opposing Actions of Angiotensin-(1-7) and Angiotensin II in the Brain of Transgenic Hypertensive Rats

Cited by 81 publications

References 38 publications

Distinct roles for ANG II and ANG-(1–7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes

Distinct roles for ANG II and ANG-(1–7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes

Enhanced Renal Immunocytochemical Expression of ANG-(1-7) and ACE2 During Pregnancy

Cardiac Angiotensin-(1-7) in Ischemic Cardiomyopathy

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