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Ping Zhu, Pollob Kumar Shil, Wen-tao Deng, Jie Li, Amrisha Verma, Tuhina Prasad, Qiuhong Li; The neuroprotection of Angiotensin-(1-7) in Tg(RHO P347S) and rd10 mice. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6187.
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Ang-(1-7) is an endogenous peptide that counter-regulates the effect of Angiotensin II and produces vasodilation, anti-inflammation and cardioprotection. In addition, Ang-(1-7) also confers cerebroprotection against ischemia and improves learning and memory. These effects are mediated by Mas receptor. We recently show that Mas receptor is expressed in both adult and developing mouse retina, more abundant in retinal neurons than endothelial and muller glial cells. We hypothesize that increased Ang-(1-7) would confer retinal neuroprotection and slow photoreceptor degeneration. We tested this hypothesis in two different animal models of photoreceptor degeneration: Tg(RHO P347S) and rd10 mice, by intraocular delivery of AAV vector expressing Ang-(1-7).
The Tg(RHO P347S) pups were injected with 1 μl (1× 1012 vg/ml) of AAV2 vector expressing secreted form of Ang-(1-7) intravitreally in right eyes on postnatal day 10-15 (P10-15) and rd10 pups on P9. The left contralateral eyes served as untreated controls. Full-field rod- and cone-mediated ERG were recorded at P60 for Tg(RHO P347S) and 6 wk for rd10 mice. A series of increasing flash intensities (−3.7,-1.7,−0.7, 0.3, 2.3, and 2.8 log cds/m2) were recorded after overnight dark adaptation. Photopic recordings were taken after mice were adapted to a white background light of 2.8 log cd/m2 for 5 min. Rod and cone photoreceptor degeneration was evaluated by immunofluorescence staining, in situ apoptosis detection and histology.
There was no significant difference between treated and untreated eyes in rod-driven scotopic ERG responses in both models. However cone-driven photopic ERG was significantly improved in Ang-(1-7)-AAV treated eyes. The average cone b-wave amplitude of Tg(RHO P347S) mice was 140.38 ± 32.76 μV in injected eyes versus 119.65 ± 24.78 μV in untreated eyes at 2.8 log cds/m2(n=6). The average cone b-wave amplitude of rd10 was 206.37 ± 24.87 μV in injected eyes versus 173.67 ± 24.42 μV in untreated eyes at 2.8 log cds/m2 (n=3). Ang-(1-7)-AAV vector treated eyes also show significantly reduced cone photoreceptor loss detected by cone opsin staining compared to untreated eyes.
Increased ocular expression of Ang-(1-7) slowed the progression cone photoreceptor degeneration in both Tg(RHO P347S) and rd10 mice, supporting the protective role of Ang-(1-7) in the retina and this approach may provide a general strategy for neuroprotection.
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