Effects of renin-angiotensin system blockade on renal angiotensin-(1-7) forming enzymes and receptors

Ferrario, Carlos M.; Jessup, Jewell A.; Gallagher, Patricia E.; Averill, David B.; Brosnihan, K. Bridget; Tallant, E. Ann; Smith, Ronald D.; Chappell, Mark C.

doi:10.1111/j.1523-1755.2005.00675.x

Cited by 242 publications

(266 citation statements)

References 35 publications

(58 reference statements)

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“…This possibility was explored by our recent experiments in which ACE2 gene expression and activity was measured in the renal cortex of rats submitted to the same treatment protocols described above ( Figure 2C and 2D). 49 In these studies, renal cortex ACE2 mRNA was not changed by 12-day administration of lisinopril, losartan, or both drugs combined, although ACE2 activity was significantly increased by either treatment alone. 49 The demonstration of a tissue-specific regulation of ACE2 gene expression and ACE2 enzyme activity is additionally underscored by our finding of a differential effect of AT 1 receptor blockade on ACE2 mRNA in the aorta and carotid arteries of SHR.…”

Section: Ace2 and Ang-(1-7)mentioning

confidence: 81%

“…49 In these studies, renal cortex ACE2 mRNA was not changed by 12-day administration of lisinopril, losartan, or both drugs combined, although ACE2 activity was significantly increased by either treatment alone. 49 The demonstration of a tissue-specific regulation of ACE2 gene expression and ACE2 enzyme activity is additionally underscored by our finding of a differential effect of AT 1 receptor blockade on ACE2 mRNA in the aorta and carotid arteries of SHR. In this study, we showed increased ACE2 gene expression in the aorta but not the carotid arteries of SHRs given olmesartan for 2 weeks.…”

Section: Ace2 and Ang-(1-7)mentioning

confidence: 81%

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Angiotensin-Converting Enzyme 2 and Angiotensin-(1-7)

2006

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Abstract-This lecture summarizes the chronology and rationale that led to the discovery of angiotensin-(1-7) as a hormone that, in its own right, opposes the vasoconstrictor and proliferative actions of angiotensin II. The work discussed here additionally analyzes the newest findings on angiotensin-converting enzyme 2, the angiotensin-converting enzyme homologue that efficiently hydrolyzes angiotensin II into angiotensin-(1-7). Both components of this system may significantly influence our future perspective of the role of the renin-angiotensin system, not just in terms of its role in the regulation of cardiovascular and renal function but, moreover, as regulators of a vast array of disease processes in which inflammation and immune mechanisms play a role.

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Section: Ace2 and Ang-(1-7)mentioning

confidence: 81%

Section: Ace2 and Ang-(1-7)mentioning

confidence: 81%

Angiotensin-Converting Enzyme 2 and Angiotensin-(1-7)

2006

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“…Imidapril increased the expression of renin mRNA probably through a negative feedback mechanism; however, it did not change the level of ANG, ACE or AT1-R mRNA, which is consistent with the results of an earlier report. 35 Fasudil did not affect the expression of ANG, renin or ACE mRNA, but slightly decreased that of AT1-R mRNA. We earlier reported that fasudil improved renal impairment in a salt-induced hypertensive rat model without changing plasma renin activity.…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of a combination of Rho-kinase inhibitor and ACE inhibitor on tubulointerstitial fibrosis induced by unilateral ureteral obstruction

et al. 2010

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We and others recently reported that long-term Rho-kinase inhibition has renoprotective effects. This study was designed to compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (imidapril), a Rho-kinase inhibitor (fasudil) and a combination of them both on renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO). We also attempted to elucidate the mechanism involved. Imidapril (50 mg l -1 ), fasudil (1 g l -1 ) or a combination of them both was given in drinking water to mice, and their effects were compared on renal interstitial fibrosis induced by UUO. We assessed histological findings, monocyte/macrophage infiltration, myofibroblast differentiation, oxidative stress and the expression of various mRNA in the kidney by UUO. Eleven days after UUO, wild-type kidney was characterized by increased fibrotic area, dihydroethidium (DHE)-positive area, a-smooth muscle actin (SMA)-positive area, F4/80-positive area and the increased expression of various mRNA. Fasudil and imidapril similarly improved fibrotic area (À23%, À15%), DHE-positive area (À13%, À11%), a-SMA-positive area (À22%, À15%), F4/80-positive area (À42%, À34%) and the expression of various mRNA, most of which were significant (Po0.05). The combination of imidapril and fasudil further improved fibrotic area (À52%), DHE-positive area (À26%), a-SMApositive area (À33%), F4/80-positive area (À62%) and the expression of various mRNA (all Po0.05 vs. monotherapy). Compared with either agent alone, the combination of an ACE inhibitor and a Rho-kinase inhibitor was more effective for the prevention of renal interstitial fibrosis because of the inhibition of transforming growth factor-b/collagen, monocyte/macrophage infiltration, myofibroblast differentiation, inflammation and the oxidative stress pathway.

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“…The interaction between ACE and ACE2 is demonstrated by the observation that ACE inhibition results in elevation of Ang 1-7 in vivo and blockade of Ang 1-7 with a specific antagonist reverses the antihypertensive effects of lisinopril. 4,6,18 Furthermore, a recent study demonstrated that lentiviral delivery of ACE2 can reverse cardiac hypertrophy in rats, suggesting not only that ACE2 is beneficial, but that manipulation of ACE2 may have therapeutic potential. 19 Direct evidence for ACE2 in the development of hypertensive cardiopathy and kidney disease comes from the ACE2 gene knockout mice.…”

Section: Discussionmentioning

confidence: 99%

“…4 Further, in rats treated with ACE inhibitors and angiotensin receptor blockers, an increase in local renal ACE2 activity is noted. 5,6 We have shown earlier that ACE is up-regulated in human diabetic nephropathy accompanied with hypertension, a condition associated with high Ang II levels. 7 Taken together, these findings suggest that there may be an alteration in the ACE/ACE2 balance in hypertension in a manner that favors increased Ang II generation (ie, upregulation of ACE) and decreased Ang II degradation (ie, down-regulation of ACE2) during hypertension.…”

mentioning

confidence: 99%

Angiotensin II Up-Regulates Angiotensin I-Converting Enzyme (ACE), but Down-Regulates ACE2 via the AT1-ERK/p38 MAP Kinase Pathway

Koka

Huang

Chung

et al. 2008

The American Journal of Pathology

261

258

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The recent discovery of the angiotensin II (Ang II)-breakdown enzyme, angiotensin I converting enzyme (ACE) 2, suggests the importance of Ang II degradation in hypertension. The present study explored the signaling mechanism by which ACE2 is regulated under hypertensive conditions. Real-time PCR and immunohistochemistry showed that ACE2 mRNA and protein expression levels were high, whereas ACE expression levels were moderate in both normal kidney and heart. In contrast, patients with hypertension showed marked ACE up-regulation and ACE2 down-regulation in both hypertensive cardiopathy and, particularly, hypertensive nephropathy. The inhibition of ACE2 expression was shown to be associated with ACE up-regulation and activation of extracellular regulated (ERK)1/2 and p38 mitogen-activated protein (MAP) kinases. In vitro, Ang II was able to upregulate ACE and down-regulate ACE2 in human kidney tubular cells, which were blocked by an angiotensin II (AT)1 receptor antagonist (losartan), but not by an AT2 receptor blocker (PD123319). Furthermore, blockade of ERK1/2 or p38 MAP kinases by either specific inhibitors or a dominant-negative adenovirus was able to abolish Ang II-induced ACE2 down-regulation in human kidney tubular cells. In conclusion, Ang II is able to up-regulate ACE and down-regulate ACE2 expression levels under hypertensive conditions both in vivo and in vitro. The AT1 receptor-mediated ERK/p38 MAP kinase signaling pathway may be a key mechanism by which Ang II down-regulates ACE2 expression, implicating an ACE/ACE2 imbalance in hypertensive cardiovascular and renal damage. The prevalence of hypertension is approximately 30% based on National Health and Nutrition Examination Survey data, 1 making it one of the most important risk factors for cardiovascular disease, the major cause of mortality in the United States.The recent discovery of the angiotensin II (Ang II) breakdown enzyme angiotensin I -converting enzyme (ACE)2 and alternative Ang II-generating pathways such as chymase, in addition to ACE, has increased the complexity of our understanding of Ang II generation and degradation in hypertension. 2,3 ACE2 is a breakdown enzyme responsible for the degradation of Ang II to Angiotensin 1-7 peptide. The later has vasodilatory properties and has its own unique receptor, the Mas receptor. 3 Emerging evidence shows that ACE2 plays an important role in negatively regulating hypertension. In rat models of hypertension, renal ACE2 mRNA and protein are decreased, although this could not be confirmed in human hypertensive nephropathy in a prior study. 4 Further, in rats treated with ACE inhibitors and angiotensin receptor blockers, an increase in local renal ACE2 activity is noted. 5,6 We have shown earlier that ACE is up-regulated in human diabetic nephropathy accompanied with hypertension, a condition associated with high Ang II levels. 7 Taken together, these findings suggest that there may be an alteration in the ACE/ACE2 balance in hypertension in a manner that favors increased Ang II generation (ie, upre...

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Effects of renin-angiotensin system blockade on renal angiotensin-(1-7) forming enzymes and receptors

Cited by 242 publications

References 35 publications

Angiotensin-Converting Enzyme 2 and Angiotensin-(1-7)

Angiotensin-Converting Enzyme 2 and Angiotensin-(1-7)

Beneficial effects of a combination of Rho-kinase inhibitor and ACE inhibitor on tubulointerstitial fibrosis induced by unilateral ureteral obstruction

Angiotensin II Up-Regulates Angiotensin I-Converting Enzyme (ACE), but Down-Regulates ACE2 via the AT1-ERK/p38 MAP Kinase Pathway

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