(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

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish
Pages (from-to)1911-1918
Number of pages8
JournalAmerican Journal of Pathology
Volume173
Issue number6
DOIs
Publication statusPublished - 2008 Dec

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Choroidal Neovascularization
Renin-Angiotensin System
Renin
Signal Transduction
Angiotensin Type 1 Receptor
Vascular Endothelial Growth Factor Receptor
Intercellular Adhesion Molecule-1
Macrophages
Losartan
Extracellular Signal-Regulated MAP Kinases
Vascular Endothelial Growth Factor A
Endothelial Cells
Vascular Endothelial Growth Factor Receptor-1
Angiotensinogen
Chemokine CCL2
Macular Degeneration
Lasers
Up-Regulation
Pharmacology
Inflammation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

(Pro)renin receptor promotes choroidal neovascularization by activating its signal transduction and tissue renin-angiotensin system. / Satofuka, Shingo; Ichihara, Atsuhiro; Nagai, Norihiro; Noda, Kousuke; Ozawa, Yoko; Fukamizu, Akiyoshi; Tsubota, Kazuo; Itoh, Hiroshi; Oike, Yuichi; Ishida, Susumu.

In: American Journal of Pathology, Vol. 173, No. 6, 12.2008, p. 1911-1918.

Research output: Contribution to journalArticle

Satofuka, Shingo ; Ichihara, Atsuhiro ; Nagai, Norihiro ; Noda, Kousuke ; Ozawa, Yoko ; Fukamizu, Akiyoshi ; Tsubota, Kazuo ; Itoh, Hiroshi ; Oike, Yuichi ; Ishida, Susumu. / (Pro)renin receptor promotes choroidal neovascularization by activating its signal transduction and tissue renin-angiotensin system. In: American Journal of Pathology. 2008 ; Vol. 173, No. 6. pp. 1911-1918.
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AU - Noda, Kousuke

AU - Ozawa, Yoko

AU - Fukamizu, Akiyoshi

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AU - Ishida, Susumu

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AB - 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.

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