|
ICHIHARA Atsuhiro
Department School of Medicine(Tokyo Women's Medical University Hospital), School of Medicine Position Professor and Division head |
|
| Article types | Original article |
| Language | English |
| Peer review | Peer reviewed |
| Title | Suppression of Choroidal Neovascularization and Fibrosis by a Novel RNAi Therapeutic Agent against (Pro)renin Receptor. |
| Journal | Formal name：Molecular therapy. Nucleic acids Abbreviation：Mol Ther Nucleic Acids ISSN code：21622531/21622531 |
| Volume, Issue, Page | 17,pp.113-125 |
| Author and coauthor | LIU Ye†, KANDA Atsuhiro*, WU Di, ISHIZUKA Erdal Tan, KASE Satoru, NODA Kousuke, ICHIHARA Atsuhiro, ISHIDA Susumu |
| Publication date | 2019/09 |
| Summary | 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. |
| DOI | 10.1016/j.omtn.2019.05.012 |
| PMID | 31254924 |