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Yiguo Qiu, Pollob Shil, Ping Zhu, Hongxia Yang, Bo Lei, Qiuhong Li; Angiotensin-Converting Enzyme 2 (ACE2) Activator DIZE Ameliorates Endotoxin-Induced Uveitis in Mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2930.
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Uveitis is a common cause of vision loss. Renin Angiotensin System (RAS) which plays a vital role in cardiovascular system is also a potent mediator of inflammation and has been implicated in pathogenesis of uveitis. The new established axis of RAS: ACE2/Ang1-7, has emerged as a novel target by counteracting the deleterious effect of Angiotensin II. The purpose of this study is to investigate the effect of ACE2 activation in protecting endotoxin induced uveitis (EIU) in mice.
ACE2 activator DIZE (Diminazene Aceturate) was administered both systemically and locally. For systemic administration, female Balb/c mice received intraperitoneal injection of DIZE (60mg/kg BW) for two days prior to LPS intravitreal injection (125ng) to induce uveitis. For local study, DIZE was given at 0.5, 0.1, and 0 mg/ml as eyedrops 6 times before LPS injection followed by 6 times in the second day. The anterior segment of the mice was examined at 12 and 24 hours after LPS injection and clinical scores were determined at the same time. Morphology and infiltrating inflammatory cells were evaluated after 24 hours. The mRNA levels of inflammatory cytokines in the retinas were analyzed by RT-PCR. ACE2 activity was determined using self-quenching fluorescent substrate.
At the 24th hour, the clinical score of mice treated with DIZE systemically was significantly lower (mean: ~1.75) than the saline vehicle group (mean: ~4) (P <0.001). Histological examination showed ~40% reduction of total infiltrating inflammatory cells in DIZE treated eyes. The CD45+ inflammatory cells in vitreous of DIZE treated group were decreased (~35%) compared to the vehicle group (P <0.05). The mRNA level of IL-6 was significantly reduced in DIZE treated group (P <0.01). The infiltrating inflammatory cells were also significantly reduced in eyes received topical administration of DIZE: 77% reduction in 0.5mg/ml group and 55% reduction in 0.1mg/ml group compared to the control group. ACE2 activity was reduced in LPS injected eyes. DIZE treatment resulted in significantly increased ACE2 activity, even more increase in wildtype eyes without LPS injection (P <0.001).
DIZE has protective effect on LPS induced ocular inflammation in EIU mouse model. These results support the notion that RAS plays a role in modulating ocular immune response and that enhancing ACE2 provides a novel therapeutic strategy for uveitis.
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