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Qiuhong Li, Pollob Kumar Shil, Amrisha Verma, Ping Zhu, Jan A Danser, Wendy W Batenburg; Suppression of ocular inflammation by a combination of renin inhibitor and prorenin receptor blocker. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6295.
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Hyperactivity of renin-angiotensin system (RAS) resulting in increased level of Angiotensin II contributes to increased vascular inflammation, oxidative stress and endothelial dysfunction. Increasing evidences also suggest that local activation of RAS may contribute to end-organ damages. Increased ocular prorenin and its receptor, PRR, have been implicated in ocular inflammation. We aimed to investigate the anti-inflammatory effect of a combined therapy of the renin inhibitor, aliskiren, and the PRR blocker, handle region peptide (HRP), in mouse endotoxin-induced uveitis (EIU) model.
Adult C57BL/6 mice were randomly divided into six groups and administered intraperitoneally with saline, aliskiren, HRP, combination of aliskiren & HRP, losartan and captopril for 3 days. EIU was induced by intravitreal injection of lipopolysaccharide (LPS) on the third day. Mice were euthanized 24h after LPS injection and the eyes were enucleated for further analysis. Infiltrations of inflammatory cells in the anterior and posterior chamber were counted. Retinal mRNA levels of pro-inflammatory cytokines were examined by RT-PCR.
Aliskiren and HRP treatments alone significantly reduced intravitreous infiltrating cells similarly (34% and 30% reduction respectively), combination of both dramatically further reduced inflammatory cell infiltration into the vitreous (69% reduction), slightly better effects than losartan (60%) and captopril (47%). The number of infiltrating inflammatory cells in the anterior chamber (AC) was also significantly reduced by aliskiren (54% reduction) and HRP (72% reduction). However combination of both did not provide additional protection (75% reduction) as seen in posterior chamber (PC) and losartan and captopril provided better protection in AC (82% and 91% respectively) than in PC. Retinal mRNA expression levels of pro-inflammatory cytokines were also significantly suppressed by the combined application of aliskiren & HRP.
These results confirmed previous findings that RAS activation is involved in the acute ocular inflammation. The additive effects of direct renin inhibition with aliskiren and inhibition of nonproteolytic activation of prorenin by HRP suggest the involvement of PRR. Since most of the inflammatory responses can be blocked by captopril and losartan, these data suggest that PRR-mediated RAS activation is largely Ang II- dependent.
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