ACE2 inhibition worsens glomerular injury in association with increased ACE expression in streptozotocin-induced diabetic mice

Soler, María José; Wysocki, Jan; Ye, M.; Lloveras, J; Kanwar, Yashpal S.; Batlle, Daniel

doi:10.1038/sj.ki.5002373

Cited by 202 publications

(219 citation statements)

References 47 publications

Supporting

Mentioning

197

Contrasting

Unclassified

Order By: Relevance

“…The high expression of ACE2 in the normal kidney (2) and the reduced expression of ACE2 in diabetic rats (16) and human kidney diseases (17,18) suggest an ACE2 involvement in diabetic nephrology. To explore the renoprotective effects of ACE2, most investigators have focused on ACE2 inhibition and demonstrated that ACE2 deficiency aggravated glomerular injury in mice (19)(20)(21). A recent study found that intraperitoneal injection of human recombinant ACE2 slowed the progression of diabetic nephropathy in diabetic mice, although exogenous proteins may cause immunity reaction after injection, which shortens its half-life (22).…”

Section: Introductionmentioning

confidence: 99%

Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

Liu

Wang

et al. 2010

Mol Med

105

View full text Add to dashboard Cite

The reduced expression of angiotensin-converting enzyme (ACE) 2 in the kidneys of animal models and patients with diabetes suggests ACE2 involvement in diabetic nephrology. To explore the renoprotective effects of ACE2 overexpression, ACE inhibition (ACEI) or both on diabetic nephropathy and the potential mechanisms involved, 50 Wistar rats were randomly divided into a normal group that received an injection of sodium citrate buffer and a diabetic model group that received an injection of 60 mg/kg streptozotocin. Eight wks after streptozotocin injection, the diabetic rats were divided into no treatment group, adenoviral (Ad)-ACE2 group, Ad-green flurescent protein (GFP) group, ACEI group receiving benazepril and Ad-ACE2 + ACEI group. Four wks after treatment, physical, biochemical, and renal functional and morphological parameters were measured. An experiment in cultured glomerular mesangial cells was performed to examine the effects of ACE2 on cellular proliferation, oxidative stress and collagen IV synthesis. In comparison with the Ad-GFP group, the Ad-ACE2 group exhibited reduced systolic blood pressure, urinary albumin excretion, creatinine clearance, glomeruli sclerosis index and renal malondialdehyde level; downregulated transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF) and collagen IV protein expression; and increased renal superoxide dismutase activity. Ad-ACE2 and ACEI had similar effects, whereas combined use of Ad-ACE2 and ACEI offered no additional benefits. ACE2 transfection attenuated angiotensin (Ang) II-induced glomerular mesangial cell proliferation, oxidative stress and collagen IV protein synthesis. In conclusion, ACE2 exerts a renoprotective effect similar to that of ACEI treatment. Decreased renal Ang II, increased renal Ang-(1-7) levels, and inhibited oxidative stress were the possible mechanisms involved.

show abstract

Section: Introductionmentioning

confidence: 99%

Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

Liu

Wang

et al. 2010

Mol Med

105

View full text Add to dashboard Cite

show abstract

“…Moreover, Ang-(1-7) infusion counterregulates Ang II to reduce glomerulosclerosis in experimental glomerulonephritis (Zhang et al 2010). In addition, chronic inhibition of ACE2 with in both healthy and diabetic mice led to glomerular injury and albuminuria (Soler et al 2007). It is important to highlight that the ACE levels were notably increased in this study (Soler et al 2007).…”

Section: Vascular Actions Of the Ace2/ang-(1-7)/mas Axismentioning

confidence: 62%

“…In addition, chronic inhibition of ACE2 with in both healthy and diabetic mice led to glomerular injury and albuminuria (Soler et al 2007). It is important to highlight that the ACE levels were notably increased in this study (Soler et al 2007). Moreover, ACE2 was downregulated in the cortex of mice subjected to subtotal nephrectomy (Dilauro et al 2010).…”

Section: Vascular Actions Of the Ace2/ang-(1-7)/mas Axismentioning

confidence: 63%

“…Besides its physiological relevance for kidney homeostasis, the ACE2/Ang-(1-7)/Mas axis also has an important and controversial role in renal diseases, acting as a renoprotective (Oudit et al 2006, 2010, Soler et al 2007, Pinheiro et al 2009, Burns et al 2010, Dilauro et al 2010, Zhang et al 2010, Giani et al 2011, Liu et al 2011b, Moon et al 2011, Stegbauer et al 2011, Zhong et al 2011, Barroso et al 2012, Kim et al 2012, Nadarajah et al 2012 or a proinflammatory (Esteban et al 2009, Velkoska et al 2011 agent. Briefly, Pinheiro et al (2009) reported that mice with genetic deletion of Mas developed renal dysfunction with an increase of glomerular tuft diameter and enhancement of fibronectin and collagen IV and III deposition, besides an increase of AT 1 and TGF-b expression.…”

Section: Vascular Actions Of the Ace2/ang-(1-7)/mas Axismentioning

confidence: 99%

See 1 more Smart Citation

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

Santos

Ferreira

Verano‐Braga

et al. 2012

Journal of Endocrinology

439

369

View full text Add to dashboard Cite

Angiotensin (Ang)-(1-7) is now recognized as a biologically active component of the reninangiotensin system (RAS). Ang-(1-7) appears to play a central role in the RAS because it exerts a vast array of actions, many of them opposite to those attributed to the main effector peptide of the RAS, Ang II. The discovery of the Ang-converting enzyme (ACE) homolog ACE2 brought to light an important metabolic pathway responsible for Ang-(1-7) synthesis. This enzyme can form Ang-(1-7) from Ang II or less efficiently through hydrolysis of Ang I to Ang-(1-9) with subsequent Ang-(1-7) formation by ACE. In addition, it is now well established that the G protein-coupled receptor Mas is a functional binding site for Ang-(1-7). Thus, the axis formed by ACE2/Ang-(1-7)/Mas appears to represent an endogenous counterregulatory pathway within the RAS, the actions of which are in opposition to the vasoconstrictor/ proliferative arm of the RAS consisting of ACE, Ang II, and AT 1 receptor. In this brief review, we will discuss recent findings related to the biological role of the ACE2/Ang-(1-7)/Mas arm in the cardiovascular and renal systems, as well as in metabolism. In addition, we will highlight the potential interactions of Ang-(1-7) and Mas with AT 1 and AT 2 receptors.

show abstract

“…This is consistent with recent findings that loss of ACE2 or inhibition of ACE2 promotes glomerular injury in association with up-regulation of ACE expression in type-1 diabetic mice. 30,31 Nevertheless, breakdown of this autoregulating pathway may be one mechanism of beneficial effects on hypertensive complications with ACE inhibitors and AT1 receptor antagonists.…”

Section: Adv-dn-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

262

258

View full text Add to dashboard Cite

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...

show abstract

ACE2 inhibition worsens glomerular injury in association with increased ACE expression in streptozotocin-induced diabetic mice

Cited by 202 publications

References 47 publications

Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

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

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

Contact Info

Product

Resources

About