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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.
Type: article
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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