(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, Susumu Ishida

研究成果: Article査読

57 被引用数 (Scopus)

抄録

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 RAPS 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 (ICAM-1), monocyte chemotactic protein (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.

本文言語English
ページ(範囲)1911-1918
ページ数8
ジャーナルAmerican Journal of Pathology
173
6
DOI
出版ステータスPublished - 2008 12

ASJC Scopus subject areas

  • 病理学および法医学

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