Receptor-associated prorenin system in the pathogenesis of retinal diseases

Shingo Satofuka^1,2, Atsuhiro Kanda³, Susumu Ishida^2,3

1Department of Ophthalmology, Teikyo University School of Medicine, Tokyo 173-8605, Japan, ²Laboratory of Retinal Cell Biology, Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan, ³Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan

TABLE OF CONTENTS

1. Abstract

2. Introduction

3. (Pro)renin receptor blockers

4. Pathologic roles of (pro)renin receptor in the eye

4.1. Age-related macular degeneration

4.1.1. Choroidal neovascularization (CNV) and tissue renin-angiotensin system (RAS)

4.1.2. Pathologic roles of (pro)renin receptor in CNV

4.2. Diabetic retinopathy

4.2.1. Diabetic retinopathy and tissue RAS

4.2.2. Pathologic roles of (pro)renin receptor in diabetes-induced retinal inflammation

5. Perspective

6. Acknowledgments

7. References

1. ABSTRACT

Receptor-associated prorenin system (RAPS) refers to the pathogenic mechanisms whereby prorenin binding to (pro)renin receptor ((P)RR) dually activates tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling through the receptor. Although we found significant involvement of angiotensin II type 1 receptor (AT1-R) in intraocular inflammation and neovascularization, central pathologies of age-related macular degeneration and diabetic retinopathy, the association of RAPS with these vision-threatening disorders has not been defined. (P)RR blockade to murine disease models led to significant suppression of laser-induced choroidal neovascularization and diabetes-induced retinal inflammation together with the upregulation of intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1 and vascular endothelial growth factor (VEGF). Either the genetic ablation or the pharmacological blockade of AT1-R exhibited significant reduction of choroidal and retinal abnormalities, both of which were further suppressed by (P)RR blockade. (P)RR blockade inhibited ERK activation and the production of VEGF and MCP-1, but not ICAM-1, in AT1-R-deficient mice with retinal and choroidal disorders. These recent findings indicate significant contribution of RAPS to the pathogenesis of age-related macular degeneration and diabetic retinopathy.