Antiglaucomatous Effects of the Activation of Intrinsic Angiotensin-Converting Enzyme 2

Abstract

PURPOSE.To evaluate the effects of the activation of endogenous angiotensin-converting enzyme 2 (ACE2) using the compound diminazene aceturate (DIZE) in an experimental model of glaucoma in Wistar rats.METHODS. DIZE (1 mg/kg) was administered daily, either systemically or topically, and the IOP was measured weekly. To examine the role of the Mas receptor in the effects of DIZE, the Ang-(1-7) antagonist A-779 was co-administered. Drainage of the aqueous humor was evaluated by using scintigraphy. The analysis of ACE2 expression by immunohistochemistry and the counting of retinal ganglion cells (RGCs) were performed in histologic sections. Additionally, the nerve fiber structure was evaluated by transmission electron microscopy. RESULTS.The systemic administration and topical administration (in the form of eye drops) of DIZE increased the ACE2 expression in the eyes and significantly decreased the IOP of glaucomatous rats without changing the blood pressure. Importantly, this IOP-lowering action of DIZE was similar to the effects of dorzolamide. The antiglaucomatous effects of DIZE were blocked by A-779. Histologic analysis revealed that the reduction in the number of RGCs and the increase in the expression of caspase-3 in the RGC layer in glaucomatous animals were prevented by DIZE. This compound also prevented alterations in the cytoplasm of axons in glaucomatous rats. In addition to these neuroprotective effects, DIZE facilitated the drainage of the aqueous humor. CONCLUSIONS.Our results evidence the pathophysiologic relevance of the ocular ACE2/Ang-(1-7)/Mas axis of the renin-angiotensin system and, importantly, indicate that the activation of intrinsic ACE2 is a potential therapeutic strategy to treat glaucoma.

One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina

“…Interestingly, mice that lack neprilysin develop RPE degeneration, and exhibit sub-RPE Ab deposits similar to that observed in AMD in humans [88]. ACE is also expressed in retina and vitreous humour in human and animal tissues [89]. Activation of endogenous ACE2 has been suggested as a potential therapeutic strategy for glaucoma treatment [89].…”

“…ACE is also expressed in retina and vitreous humour in human and animal tissues [89]. Activation of endogenous ACE2 has been suggested as a potential therapeutic strategy for glaucoma treatment [89]. Plasmin and its activators have also been shown to be both activated by and involved in the degradation of Ab aggregates [90].…”

The Microfibril Hypothesis of Glaucoma: Implications for Treatment of Elevated Intraocular Pressure

“…120 Recently, in a rat model of induced ocular hypertension, activation of ACE2 with diminazene aceturate was shown to prevent glaucoma and reduce IOP, possibly by increasing aqueous humor outflow. 121 Although the moderate reductions of IOP seen in humans after short-term treatment with oral or topical AT1 blockers suggest limited usefulness for this class of compounds, a slow developing phase of further reduction of IOP would be predicted by the microfibril hypothesis of glaucoma. If glaucoma is a microfibril deficiency, available evidence suggests that the accompanying chronic TGFb activation would affect IOP by remodeling ECM over an extended period of time.…”

Overexpression of Angiotensin-Converting Enzyme 2 Ameliorates Amyloid β-Induced Inflammatory Response in Human Primary Retinal Pigment Epithelium

“…29,52-54 ACE2 acts as a counter regulator of ACE in cleaving Ang II into Ang-(1-7), and exerts beneficial effects in several animal models of ocular diseases, including DR, 55 glaucoma, 56 EIU, 34,35 and EAU. 21,36 On the other hand, ACE2 deletion exaggerated Ang II-induced expressions of inflammatory cytokines.…”