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Amrisha Verma, Yunyang Wang, Ping Zhu, Pollob Kumar Shil, Tuhina Prasad, Qiuhong Li; Role of Prorenin and Prorenin receptor in ocular inflammation. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2191.
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© ARVO (1962-2015); The Authors (2016-present)
Renin-angiotensin system (RAS) plays a vital role in cardiovascular system. Growing evidences suggest that local tissue RAS hyperactivity, resulting increased Angiotensin II (Ang II) level, contributes to increased vascular inflammation, oxidative stress and endothelial dysfunction in variety of conditions including ocular diseases. Recent studies show that receptor-bound prorenin, which is highly elevated in vitreous of many ocular diseases, may be the major pathway for local Ang II production. Prorenin binding to the receptor (PRR) also activates signaling events contributing tissue damage that is independent of Ang II action. The purpose of this study was to investigate the role of prorenin and its receptor in ocular inflammation using both in vitro and in vivo systems.
Cultured human muller cells were incubated with human recombinant prorenin (100nM) in the presence or absence of RAS blockers [ACE inhibitor captopril, AT1R inhibitor losartan, siRNA-PRR and the PRR antagonist HRP (handle region peptide)]. Pro-inflammatory cytokines IL-1α, IL-6, TGF-β, TNF-α were analyzed by real time RT-PCR. The role of HRP in ocular inflammation was also investigated in vivo in endotoxin-induced uveitis (EIU) mouse model by intravitreal injection of AAV vector expressing HRP. Ocular inflammation was assessed by counting infiltrating inflammatory cells in the eyes from H&E stained sections and RT-PCR analysis of inflammatory cytokines.
Prorenin stimulated increased cytokine expression in cultured human muller cells (>10 fold increase for IL-1α, IL-6; and >2 fold increase for TGF-β, TNF-α). Prorenin stimulated increase of cytokine expression was almost completely blocked by siRNA-PRR or HRP, suggesting involvement of PRR. Losartan treatment also blocked prorenin stimulated increase of cytokine expression, suggesting that prorenin stimulated cytokine expression is largely mediated by Ang II-dependent pathway. Intraocular delivery of AAV-HRP significantly reduced LPS induced infiltration of inflammatory cells and the expression of inflammatory cytokines in mouse eyes.
These results suggest that elevated prorenin may contribute to ocular diseases by stimulating pro-inflammatory cytokine expression; this effect is mediated via the interaction with PRR and is largely Ang II- dependent. The study also suggests the potential use of HRP as a therapeutic agent to reduce ocular inflammation.
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