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

Abstract

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...

Ontogeny of angiotensin-converting enzyme 2

“…Our present findings demonstrate that Ang II, acting through AT 1 R, downregulates ACE2 mRNA expression and activity in the developing kidney. These results are consistent with the findings that Ang II decreases ACE2 gene expression and activity in neonatal cardiomyocytes and in human tubular epithelial (HK-2) cells in vitro through AT 1 R (26,27). Coordinate regulation of ACE and ACE2 by Ang II during postnatal life may represent a dual mechanism by which Ang II prevents its ACE-dependent generation from Ang I as well as inhibits its ACE2-mediated degradation to Ang-(1-7).…”

Decreased Expression of Angiotensin-Converting Enzyme 2 in Pancreatic Ductal Adenocarcinoma Is Associated with Tumor Progression

“…With the exception of the increased ANG II concentration in PDAC tissue homogenates, we also found that ANG II significantly inhibited ACE2 protein expression in BxPC3 and SW1990 cells. The AT1 receptor-mediated ERK/p38 MAP kinase signaling pathway may be a key mechanism by which ANG II downregulates ACE2 expression (Koka et al 2008). The downregulation of ACE2 by ANG II may serve as a mechanism within the pancreatic tissues to favor ANG II-mediated responses in PDAC.…”

“…As a recently reported homologue of ACE, angiotensin converting enzyme 2 (ACE2) is a new component of the updated RAS (Koka et al 2008). This enzyme is highly expressed in the endothelial cells of the heart, kidney, and testis, and mainly degrades ANG II to angiotensin 1-7 (ANG 1-7), which is thought to act as a vasodilator and is involved in apoptosis and growth arrest, in contrast to ACE activity which generates ANG II and degrades ANG 1-9 (Epelman et al 2008;Moon et al 2008;Soler et al 2008).…”

Loss of angiotensin-converting enzyme 2 enhances TGF-β/Smad-mediated renal fibrosis and NF-κB-driven renal inflammation in a mouse model of obstructive nephropathy

“…2 Increasing evidence shows that Ace2 has an essential role in the cardiovascular and kidney diseases. 1,3,4 Ace2 inhibition also leads to the development of albuminuria in a mouse model of diabetes.…”