Effect of ACE2 and angiotensin-(1–7) in a mouse model of early chronic kidney disease

Dilauro, Marc; Zimpelmann, Joseph; Robertson, Susan J.; Genest, Dominique S.; Burns, Kevin D.

doi:10.1152/ajprenal.00426.2009

Cited by 108 publications

(108 citation statements)

References 40 publications

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“…Sukumaran et al suggested that telmisartan provided beneficial protection against heart failure in rats, at least partly by suppressing inflammation, oxidative stress, and endoplasmic reticulum stress, as well as through modulation of the ACE2/Ang (1-7)-Mas axis [23] . Moreover, kidney ACE2 was shown to be downregulated in a mouse model of early chronic kidney disease [24] , whereas AT1-R antagonism of early radiation-induced changes in microglial activation or neurogenesis in normal rat brains has not been reported [25] . This discrepancy may be relevant to differences in disease conditions, the tissues involved, or the variety of ARB drugs tested.…”

Section: Discussionmentioning

confidence: 99%

Telmisartan attenuates hepatic fibrosis in bile duct-ligated rats

Liu

Wen

et al. 2012

Acta Pharmacol Sin

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Aim: To evaluate the antifibrotic effect of telmisartan, an angiotensin II receptor blocker, in bile duct-ligated rats. Methods: Adult Sprague-Dawley rats were allocated to 3 groups: sham-operated rats, model rats underwent common bile duct ligation (BDL), and BDL rats treated with telmisartan (8 mg/kg, po, for 4 weeks). The animals were sacrificed on d 29, and liver histology was examined, the Knodell and Ishak scores were assigned, and the expression of angiotensin-converting enzyme (ACE) and ACE2 was evaluated with immunohistochemical staining. The mRNAs and proteins associated with liver fibrosis were evaluated using RTQ-PCR and Western blot, respectively. Results: The mean fibrosis score of BDL rats treated with telmisartan was significantly lower than that of the model rats (1.66±0.87 vs 2.13±0.35, P=0.015). However, there was no significant difference in inflammation between the two groups, both of which showed moderate inflammation. Histologically, treatment with telmisartan significantly ameliorated BDL-caused the hepatic fibrosis. Treatment with telmisartan significantly upregulated the mRNA levels of ACE2 and MAS, and decreased the mRNA levels of ACE, angiotensin II type 1 receptor (AT1-R), collagen type III, and transforming growth factor β1 (TGF-β1). Moreover, treatment with telmisartan significantly increased the expression levels of ACE2 and MAS proteins, and inhibited the expression levels of ACE and AT1-R protein. Conclusion:Telmisartan attenuates liver fibrosis in bile duct-ligated rats via increasing ACE2 expression level.

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Section: Discussionmentioning

confidence: 99%

Telmisartan attenuates hepatic fibrosis in bile duct-ligated rats

Liu

Wen

et al. 2012

Acta Pharmacol Sin

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“…By contrast, no aggravation of renal injury produced by kidney ischemia-reperfusion was observed in Mas K/K mice, and in the same model the Mas agonist AVE 0991 reduced renal injury (Barroso et al 2012). Ang-(1-7) was also reported to stimulate (Burns et al 2010) or to inhibit ) the epithelial-to-mesenchymal transformation in tubular cells.…”

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

confidence: 90%

“…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). Administration of recombinant ACE2 diminished fibrosis, i.e.…”

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

confidence: 98%

“…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%

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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

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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.

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“…69 -72,74 -78 ANG II, CTGF, AND SIGNALING PATHWAYS Initially, CTGF was mainly understood to act downstream of TGF␤ to regulate ECM synthesis. 4,8 The Smad proteins are essential components of this intracellular signaling pathway, acting as transcription factors for TGF␤-mediated responses, including fibrosis. 73 In a rat model of remnant kidney disease, Ang II induces tubular mRNA encoding CTGF and collagen I, and the subsequent proteins are upregulated by phosphorylated Smad2/3 but downregulated by Smad7; that is, overexpression of Smad7 abolishes Ang IIinduced Smad2/3 phosphorylation and upregulation of CTGF and collagen I.…”

Section: Ang II and Ctgfmentioning

confidence: 99%

Angiotensin II as a Morphogenic Cytokine Stimulating Renal Fibrogenesis

Rüster

Wolf

2011

Journal of the American Society of Nephrology

175

150

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Chronic kidney disease (CKD) is increasing worldwide. Although the cause of its progression is multifactorial, 1-3 activation of the renin-angiotensin-aldosterone system (RAAS) is a key effector and RAAS inhibitors are among the beststudied renoprotective agents. 4 -7 Although the RAAS is complex, with new peptides such as angiotensin 1-7 and angiotensin IV exhibiting profibrotic effects by binding to specific receptors as well as observations that aldosterone and even renin itself can stimulate fibrogenesis in the kidney, 8 -12 and angiotensin II (Ang II) blockade can stimulate renin release, 13 the review presented here focuses exclusively on Ang II as the major component of the RAAS effect on morphogenesis. There are several excellent reviews covering the other components of the RAAS and their profibrotic actions in the kidney. 8 -10,14 The classic view of Ang II as a vasoactive agent involved in local and systemic hemodynamic regulation 15 needs extension to encompass its properties as a morphogenic cytokine with an active role in renal pathology. 16,17 Ang II was first described 2 decades ago as stimulating the hypertrophy of tubular cells and the associated increase in collagen secretion. 18,19 Fibrosis is the final common pathway leading to renal diseases of diverse etiology, including inflammation, hemodynamics, and metabolic injury. 20 -22 Ang II modulates renal cell growth and extracellular matrix (ECM) synthesis or degradation. 17,[23][24][25] For example, overexpression of renin and angiotensinogen in rat glomeruli leads to expanded ECM without inducing systemic hypertension. 26,27 The stimulatory effects of Ang II on increased collagen expression depend on various mechanisms. In addition to angiotensin-converting enzyme (ACE), which is the most well known enzyme capable of Ang II formation, other non-ACE Ang II-generating pathways are currently under study. 28 ACE inhibitors also diminish cellular infiltrates and inflammatory markers in many models of renal injury. 29 ANG II AND TGF␤The interactions between Ang II and the TGF␤ axis are multiple and complex (Figure 1). 29 -31 TGF␤ is a fibrogenic and anti-inflammatory cytokine and plays a critical role in the pathophysiology of renal injury. 32,33 Ang II stimulates transcription and synthesis of TGF␤, particularly TGF␤1, in cultured murine proximal tubular cells and also upregulates specific receptors for TGF␤, further enhancing its profibrogenic action. 34 -36 Ang II directly stimulates complex interactions in the ABSTRACTInhibitors of the renin-angiotensin-aldosterone system attenuate glomerulosclerosis and interstitial fibrosis. Although the mechanisms underlying their antifibrotic effects are complex, angiotensin II (Ang II) emerges as a major profibrogenic cytokine. Ang II modulates renal cell growth, extracellular matrix synthesis, and degradation by multiple fibrotic pathways. One of the main targets of Ang II in renal fibrosis is TGF␤. Many, but not all, of the stimulatory effects of Ang II on fibrogenesis depend on the induction...

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Effect of ACE2 and angiotensin-(1–7) in a mouse model of early chronic kidney disease

Cited by 108 publications

References 40 publications

Telmisartan attenuates hepatic fibrosis in bile duct-ligated rats

Telmisartan attenuates hepatic fibrosis in bile duct-ligated rats

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

Angiotensin II as a Morphogenic Cytokine Stimulating Renal Fibrogenesis

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