Abstract
Purpose: :
Angiotensin II receptor blockade improves vascular and glial pathology in experimental retinopathy of prematurity (ROP). We examined if a prorenin receptor [(P)RR] against the handle region of prorenin (HRP), improves vascular pathology and losses in retinal function in ROP, and influences the developing retina.
Methods: :
ROP was induced in Sprague Dawley rats (80%:21% O2, 22:2 hours/day) from postnatal day (P) 0-11, and room air P12-18. Shams were in room air from P0-18. HRP (0.1mg/kg, osmotic pump) was given P12-18 and compared with the angiotensin type 1 receptor blocker, valsartan (10 mg/kg/day, gavage)(N=6 to 10 rats/group). Vascular pathology was assessed in paraffin sections by counting blood vessels in the inner retina, and leukocytes in retinal vessels after in vivo perfusion with Concavanalin-rhodamine A. Quantitative real-time PCR was used to measure (P)RR, vascular endothelial growth factor (VEGF) and intracellular adhesion molecule-1 (ICAM-1) mRNA in retina. Immunohistochemistry for phosphorylated ERK 1/2 (p-ERK 1/2) was performed in paraffin sections, and retinal function measured with the electroretinogram (ERG).
Results: :
Using in situ hybridisation and immunohistochemistry, the (P)RR was localised to ganglion cells and the inner nuclear layer (INL). ROP was associated with an increase in angiogenesis, leukostasis, mRNA for (P)RR, VEGF and ICAM-1 and p-ERK 1/2 immunolabelling in ganglion cells and the INL, while losses occurred in retinal function compared to sham controls. In ROP, HRP had differential effects on the vasculature compared to neurons and glia, by reducing vascular pathology and the expression of growth factors, but not altering p-ERK 1/2 immunolabelling, and worsening the ERG. In ROP, valsartan had similar vasculoprotective effects as HRP, but unlike HRP reduced p-ERK 1/2 immunolabelling and did not affect retinal function. These damaging effects of the HRP on neurons and glia in ROP also occurred in the developing retina of shams and was associated with an increase in (P)RR mRNA. In contrast, valsartan reduced p-ERK 1/2 immunolabelling and had no effect on retinal function in shams.
Conclusions: :
These findings indicate that the HRP provides vascular protection in ROP; however, HRPs detrimental effects on neurons and glia in both ROP and developing retina may indicate that the (P)RR has a fundamental role in retinal function.
Keywords: retinopathy of prematurity • retinal neovascularization • retinal development