Role of prorenin in the pathogenesis of retinal neovascularization.
OBJECTIVE
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.
Yokota
Harumasa
H
Department of Ophthalmology, Asahikawa Medical College, Asahikawa 078-8510, Japan.
Takamiya
Akira
A
Nagaoka
Taiji
T
Hikichi
Taiichi
T
Ishida
Yuichi
Y
Suzuki
Fumiaki
F
Yoshida
Akitoshi
A
D043925:Angiogenesis Inducing Agents / Q000032:analysis; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002216:Captopril / Q000494:pharmacology; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D012083:Renin / Q000502:physiology*; D012160:Retina / Q000737:chemistry; D015861:Retinal Neovascularization / Q000209:etiology*; D012178:Retinopathy of Prematurity / Q000378:metabolism; D000093342:Prorenin Receptor
D043925:Angiogenesis Inducing Agents; D000806:Angiotensin-Converting Enzyme Inhibitors; D009842:Oligopeptides; D010455:Peptides; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C530358:handle-region peptide, mouse; D002216:Captopril; D012083:Renin; D000093342:Prorenin Receptor