title: (Pro)renin receptor promotes choroidal neovascularization by activating its signal transduction and tissue renin-angiotensin system.
abstract: The receptor-associated prorenin system (RAPS) refers to pathogenic mechanisms whereby prorenin binding to its receptor activates both the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling pathways. Although we found significant involvement of angiotensin II type 1 receptor (AT1-R)-mediated inflammation in choroidal neovascularization (CNV), a central abnormality of vision-threatening age-related macular degeneration, the association of receptor-associated prorenin system with CNV has not been defined. Here, (pro)renin receptor blockade in a murine model of laser-induced CNV led to the significant suppression of CNV together with macrophage infiltration and the up-regulation of intercellular adhesion molecule-1, (ICAM-1) monocyte chemotactic protein-1, (MCP-1) vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1, and VEGFR-2. To clarify the role of signal transduction via the (pro)renin receptor in CNV, we used mice in which renin-angiotensin system was deactivated by either the pharmacological blockade of AT1-R with losartan or the genetic ablation of AT1-R or angiotensinogen. Compared with wild-type controls, these mice exhibited significant reduction of CNV and macrophage infiltration, both of which were further suppressed by (pro)renin receptor blockade. The (pro)renin receptor and phosphorylated extracellular signal-regulated kinases (ERK) were co-localized in vascular endothelial cells and macrophages in CNV. (Pro)renin receptor blockade suppressed ERK activation and the production of MCP-1 and VEGF, but not ICAM-1, VEGFR-1, or VEGFR-2, in AT1-R-deficient mice with CNV and in losartan-treated microvascular endothelial cells and macrophages. These results indicate the significant contribution of RAPS to CNV pathogenesis.
authors.affiliation: Laboratory of Retinal Cell Biology, Inaida Endowed Department of Anti-Aging Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Satofuka
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Ichihara
authors.forename: Norihiro
authors.initials: N
authors.lastname: Nagai
authors.forename: Kousuke
authors.initials: K
authors.lastname: Noda
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ozawa
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tsubota
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishida
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012083:Renin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000093342:Prorenin Receptor
chemical_list: D018932:Chemokine CCL2; D044140:Receptor, Angiotensin, Type 1; D011956:Receptors, Cell Surface; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D048049:Extracellular Signal-Regulated MAP Kinases; D012083:Renin; D000093342:Prorenin Receptor