A Peptide Corresponding to Handle Region for Nonproteolytic Activation of Prorenin Inhibits Retinal Neovascularization in a Retinopathy of Prematurity Model

Abstract

Abstract: : Purpose: To investigate the role of prorenin in the pathogenesis of retinal neovascularization, we evaluated an inhibitory effect of the peptide to cover the "handle" region in the mouse prorenin prosegment, the handle region peptide (HRP), on retinal neovascularization. Methods: Neonatal C57BL6 mice were exposed to 75% oxygen from postnatal day 7 (P7) to P12 and then placed in room air. The animals received HRP (1.0 or 0.1 mg/kg/day), captopril (10 mg/kg/day), or normal saline daily from P12 to P17. The animals were killed on P17. Enucleated eyes were used for whole–mount retina and retinal sections and freshly extracted retina for semiquantitative analysis of mRNA of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), Flt–1, Flk–1, angiopoietin 2, and Tie2. Results: The average number of neovascular nuclei in ROP treated with normal saline, captopril, HRP (0.1 mg/kg/day) and HRP (1.0 mg/kg/day) were 37.2 ± 8.6 (mean ± SD) (n=6), 7.7 ± 3.4 (n=6), 39.5 ± 7.3 (n=6), and 6.5 ± 2.7 (n=6), respectively. Rhodamine perfused retina also demonstrated that HRP (1.0 mg/kg/day), and captopril inhibited neovascular formation. HRP (0.1 mg/kg/day) did not show an inhibitory effect on neovascularization. Semiquantitative analysis of mRNA for angiogenic factors showed that HRP (1.0 mg/kg/day) inhibited overexpression of PlGF, Flt–1, and angiopoietin 2. Conclusions: HRP inhibits development of retinal neovascularization thorough interfering nonproteolytic activation of prorenin. This indicates that prorenin may promote retinal neovascularization in proliferative diabetic retinopathy and retinopathy of prematurity.

Keywords: retinal neovascularization • retinopathy of prematurity • diabetic retinopathy