May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
(Pro)renin Receptor Promotes Choroidal Neovascularization by Dually Activating Its Signal Transduction and Tissue Renin-Angiotensin System
Author Affiliations & Notes
  • S. Satofuka
    Keio University School of Medicine, Tokyo, Japan
    Laboratory of Retinal Cell Biology,
    Department of Ophthalmology,
  • A. Ichihara
    Keio University School of Medicine, Tokyo, Japan
    Department of Internal Medicine,
  • N. Nagai
    Keio University School of Medicine, Tokyo, Japan
    Laboratory of Retinal Cell Biology,
    Department of Ophthalmology,
  • K. Noda
    Keio University School of Medicine, Tokyo, Japan
    Laboratory of Retinal Cell Biology,
    Department of Ophthalmology,
  • Y. Ozawa
    Keio University School of Medicine, Tokyo, Japan
    Laboratory of Retinal Cell Biology,
    Department of Ophthalmology,
  • A. Fukamizu
    Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan
  • K. Tsubota
    Keio University School of Medicine, Tokyo, Japan
    Department of Ophthalmology,
  • H. Itoh
    Keio University School of Medicine, Tokyo, Japan
    Department of Internal Medicine,
  • Y. Oike
    Keio University School of Medicine, Tokyo, Japan
    Laboratory of Retinal Cell Biology,
    Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
  • S. Ishida
    Keio University School of Medicine, Tokyo, Japan
    Laboratory of Retinal Cell Biology,
    Department of Ophthalmology,
  • Footnotes
    Commercial Relationships  S. Satofuka, None; A. Ichihara, None; N. Nagai, None; K. Noda, None; Y. Ozawa, None; A. Fukamizu, None; K. Tsubota, None; H. Itoh, None; Y. Oike, None; S. Ishida, None.
  • Footnotes
    Support  the Japanese Ministry of Education, Culture, Sports, Science and Technology (grant-in-aid for scientific research no. 18791296 to S.S.)
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 5881. doi:
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      S. Satofuka, A. Ichihara, N. Nagai, K. Noda, Y. Ozawa, A. Fukamizu, K. Tsubota, H. Itoh, Y. Oike, S. Ishida; (Pro)renin Receptor Promotes Choroidal Neovascularization by Dually Activating Its Signal Transduction and Tissue Renin-Angiotensin System. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5881.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Receptor-associated prorenin system (RAPS) refers to the pathogenic mechanism whereby prorenin binding to its receptor dually activates intracellular signaling and tissue renin-angiotensin system (RAS). Recently, 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 (AMD). The aim of the present study was to define the association of RAPS with CNV.

Methods: : Laser photocoagulation was used to induce CNV in C57BL/6 mice, angiotensinogen- or AT1-R-deficient mice. Animals received intraperitoneal injections of vehicle or (pro)renin receptor blocker (PRRB) the day before photocoagulation and the treatment were continued daily till the end of the study. CNV response was analyzed by volumetric measurements using confocal microscopy 1 week after laser injury. The retinal pigment epithelium-choroidal protein levels of intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1, vascular endothelial growth factor (VEGF), and VEGF receptor (VEGFR)-1 and VEGFR-2 were examined by ELISA.

Results: : PRRB treatment led to significant suppression of CNV together with the upregulation of ICAM-1, MCP-1, VEGF and its receptors. To clarify the role of signal transduction via (pro)renin receptor in CNV, we used angiotensinogen- or AT1-R-deficient mice in which RAS was deactivated. Compared to wild-type controls, these mice exhibited significant reduction of CNV, which was further suppressed by PRRB. PRRB suppressed the activation of ERK and the production of VEGF and MCP-1 in AT1-R-deficient mice with CNV.

Conclusions: : These results indicate significant contribution of RAPS to the pathogenesis of CNV, suggesting the possibility of PRRB as a novel, therapeutic strategy for AMD.

Keywords: age-related macular degeneration • pathology: experimental • inflammation 
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