Role of Prorenin in the Pathogenesis of Retinal Neovascularization

Purpose: To determine the role of prorenin in the pathogenesis of retinal neovascularization, we evaluated the inhibitory effect of 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 placed in room air. The animals received HRP (1.0 or 0.1 mg/kg/day), captopril (10 mg/kg/day), or normal saline from P12 to P17. Following enucleation of the eyes, the retina was dissected for whole-mount retinal sections and semiquantitative analysis of mRNA of vascular endothelial growth factor (VEGF), placental growth factor (PIGF), fms-like tyrosine kinase 1 (Flt-1), fetal liver kinase 1 (Flk-1), angiopoietin 2 (Ang2), and tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (Tie2).

Results: The average numbers of neovascular nuclei in retinopathy of prematurity treated with normal saline, captopril, and HRP (0.1 or 1.0 mg/kg/day) were 37.2+/-8.6, 7.7+/-3.4, 39.5+/-7.3, and 6.5+/-2.7, respectively. HRP (1.0 mg/kg/day) and captopril inhibited neovascularization in rhodamine-perfused retina; HRP (0.1 mg/kg/day) did not. Semiquantitative analysis of mRNA for angiogenic factors showed that HRP (1.0 mg/kg/day) inhibited overexpression of PIGF, Flt-1, and Ang2.

Conclusions: HRP inhibits retinal neovascularization by interfering with nonproteolytic activation of prorenin, indicating that prorenin may promote retinal neovascularization.