June 2014
Volume 55, Issue 6
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Research Highlight  |   June 2014
Angiotensin-Converting Enzyme 2: Potential Target for the Development of Novel Ocular Therapies
Investigative Ophthalmology & Visual Science June 2014, Vol.55, 3819. doi:10.1167/iovs.14-14847
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      Anderson José Ferreira; Angiotensin-Converting Enzyme 2: Potential Target for the Development of Novel Ocular Therapies. Invest. Ophthalmol. Vis. Sci. 2014;55(6):3819. doi: 10.1167/iovs.14-14847.

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      © ARVO (1962-2015); The Authors (2016-present)

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The concept of the renin-angiotensin system (RAS) is now beyond what we imagined few years ago. New components have been incorporated into its enzymatic cascade, which has brought promising perspectives to the pathophysiology of many diseases. Specifically, it is well established that the axis of the RAS formed by angiotensin-converting enzyme (ACE) 2, angiotensin(Ang)-(1-7), and Mas receptor balances the deleterious actions triggered by the overactivation of the ACE/Ang II/AT1 receptor branch of the RAS. 1 Thus, these recent discoveries represent the existence of an endogenous mechanism to balance many physiological actions, thereby increasing the possibility of developing new therapeutic strategies. 
These new findings have allowed impressive advances in many medical specialties, like cardiology, nephrology, and endocrinology. Nowadays, this knowledge is evident in the ophthalmology field. Angiotensin-converting enzyme 2 activators such as the compound diminazene aceturate (DIZE) are small molecules discovered using a conformational-based drug design strategy by applying a virtual screening approach. 2 Recently, we have found that DIZE has beneficial effects on glaucoma through a mechanism involving the Mas receptor, neuroprotection, and drainage of the aqueous humor. 3  
It is in this regard that the study of Qiu et al. 4 in this issue of IOVS is of great significance. The authors demonstrated that activation of intrinsic ACE2 using DIZE induces beneficial effects on uveitis induced by intravitreal injection of lipopolysaccharide. These results reinforce the relevance of the ocular ACE2/Ang-(1-7)/Mas axis of the RAS in the pathophysiology of the eyes. One important issue, however, that must be resolved before this could be successfully translated into therapeutics is the mechanism of actions by which ACE2 activation prevents uveitis. For instance, is the whole ACE2/Ang-(1-7)/Mas axis involved in this effect, or it is an off-target action of ACE2? 
In summary, the study provides further evidence for the importance of ACE2 in ocular diseases, thereby suggesting that this enzyme is a potential target for the development of novel ocular therapies. 
References
Ferreira AJ Santos RAS Bradford CN Therapeutic implications of the vasoprotective axis of the renin-angiotensin system in cardiovascular diseases. Hypertension . 2010; 55: 207–213. [CrossRef] [PubMed]
Kulemina LV Ostrov DA. Prediction of off-target effects on angiotensin-converting enzyme 2. J Biomol Screen . 2011; 16: 878–885. [CrossRef] [PubMed]
Foureaux G Nogueira JC Nogueira BS Antiglaucomatous effects of the activation of intrinsic angiotensin-converting enzyme 2. Invest Ophthalmol Vis Sci . 2013; 54: 4296–4306. [CrossRef] [PubMed]
Qiu Y Shil PK Zhu P Angiotensin-converting enzyme 2 (ACE2) activator diminazene aceturate ameliorates endotoxin-induced uveitis in mice. Invest Ophthalmol Vis Sci . 2014; 55: 3809–3818. [CrossRef] [PubMed]
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