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Suppression of Choroidal Neovascularization and Fibrosis by a Novel RNAi Therapeutic Agent against (Pro) renin Receptor
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Title: | Suppression of Choroidal Neovascularization and Fibrosis by a Novel RNAi Therapeutic Agent against (Pro) renin Receptor |
Authors: | Liu, Ye Browse this author | Kanda, Atsuhiro Browse this author →KAKEN DB | Wu, Di Browse this author | Ishizuka, Erdal Tan Browse this author | Kase, Satoru Browse this author →KAKEN DB | Noda, Kousuke Browse this author →KAKEN DB | Ichihara, Atsuhiro Browse this author →KAKEN DB | Ishida, Susumu Browse this author →KAKEN DB |
Issue Date: | 6-Sep-2019 |
Publisher: | Cell Press |
Journal Title: | Molecular therapy. Nucleic acids |
Volume: | 17 |
Start Page: | 113 |
End Page: | 125 |
Publisher DOI: | 10.1016/j.omtn.2019.05.012 |
Abstract: | The receptor-associated prorenin system refers to the pathogenic mechanism whereby prorenin binding to (pro) renin receptor [(P) RR] dually activates the tissue renin-angiotensin system (RAS) and RAS-independent signaling, and its activation contributes to the molecular pathogenesis of various ocular diseases. We recently developed a new single-stranded RNAi agent targeting both human and mouse (P) RR ((P) RR-proline-modified short hairpin RNA [(P) RR-PshRNA]), and confirmed its therapeutic effect on murine models of ocular inflammation. Here, we investigated the efficacy of (P) RR-PshRNA against laser-induced choroidal neovascularization (CNV) and subretinal fibrosis, both of which are involved in the pathogenesis of age-related macular degeneration (AMD). Administration of (P) RR-PshRNA in mice significantly reduced CNV formation, together with the expression of inflammatory molecules, macrophage infiltration, and extracellular signal-regulated kinase (ERK) 1/2 activation. In addition, (P) RR-PshRNA attenuated subretinal fibrosis, together with epithelial-mesenchymal transition (EMT)-related markers including phosphorylated SMAD2. The suppressive effect of (P) RR-PshRNA is comparable with aflibercept, an anti-vascular endothelial growth factor drug widely used for AMD therapy. AMD patient specimens demonstrated (P) RR co-localization with phosphorylated ERK1/2 in neovascular endothelial cells and retinal pigment epithelial cells. These results indicate that (P) RR contributes to the ocular pathogenesis of both inflammation-related angiogenesis and EMT-driven fibrosis, and that (P) RR-PshRNA is a promising therapeutic agent for AMD. |
Rights: | https://creativecommons.org/licenses/by/4.0/ |
Type: | article |
URI: | http://hdl.handle.net/2115/76030 |
Appears in Collections: | 医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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