Angiotensin-converting Enzyme2(ACE2) Activator Dize Ameliorates Endotoxin-induced Uveitis in Mice
|School||Chongqing Medical University|
|Keywords||endotoxin induced uveitis angiotensin-convertingenzyme2 renin angiotensin system diminazene aceturate retina|
PURPOSE: To investigate whether the activation of endogenousangiotensin-converting enzyme2(ACE2) would protect mice fromendotoxin induced uveitis (EIU).METHODS: For systemic administration, female BALB/c micereceived intraperitoneal injection of DIZE (60mg/kg BW) for two daysprior to LPS intravitreal injection (125ng) to induce uveitis. For localadministration, DIZE was given at0.5,0.1, and0mg/ml as eyedrops6times before LPS(15ng) injection followed by6times in the second day.The anterior segment of the mice was examined at12and24hours afterLPS injection and clinical scores were determined at the same time.Morphology and infiltrating inflammatory cells were evaluated after24hours. The mRNA levels of inflammatory cytokines of the eyes wereanalyzed by RT-PCR. ACE2activity was determined usingself-quenching fluorescent substrate.RESULTS: At the24th hour, the clinical score of mice treatedwith DIZE systemically was significantly lower (1.75±0.96, mean±SD) than the saline vehicle group (4.00±1.22, mean±SD)(p<0.001).Histological examination showed40%reduction of total infiltratinginflammatory cells in DIZE treated eyes. The CD45+inflammatory cellsin vitreous of DIZE treated group were decreased (33.65%) compared tothe vehicle group (p<0.05). The mRNA level of ICAM-1、TNF-α (p<0.01)、 MCP-1、 IL-6(p<0.001) was significantly reduced in DIZEtreated group. The infiltrating inflammatory cells were also significantlyreduced in eyes received topical administration of DIZE:77%reductionin0.5mg/ml group and55%reduction in0.1mg/ml group compared tothe control group. ACE2activity was reduced in LPS injected eyes.DIZE treatment resulted in significantly increased ACE2activity, evenmore increase in wildtype eyes without LPS injection (p <0.001).CONCLUSIONS: DIZE has protective effect on LPS inducedocular inflammation in EIU mouse model. These results support thenotion that enhancing ACE2plays a role in modulating ocularinflammatory response and that regulating local RAS provides a noveltherapeutic strategy for uveitis.