Published online before print October 30, 2008

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(American Journal of Pathology. 2008;173:1911-1918.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080457

(Pro)renin Receptor Promotes Choroidal Neovascularization by Activating Its Signal Transduction and Tissue Renin-Angiotensin System

Shingo Satofuka^*, Atsuhiro Ichihara, Norihiro Nagai^*, Kousuke Noda^*, Yoko Ozawa^*, Akiyoshi Fukamizu, Kazuo Tsubota, Hiroshi Itoh, Yuichi Oike^¶ and Susumu Ishida^*||

From the Laboratory of Retinal Cell Biology,^* and Departments of Ophthalmology and Internal Medicine, Keio University School of Medicine, Tokyo; Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba; Department of Molecular Genetics,^¶ Graduate School of Medical Sciences, Kumamoto University, Kumamoto; Inaida Endowed Department of Anti-Aging Ophthalmology,|| Keio University School of Medicine, Tokyo, Japan

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.

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