Aldose reductase deficiency protects retinal neurons against oxygen-induced retinopathy

Abstract

PURPOSE: Retinopathy of prematurity (ROP) has become the leading cause of blindness and visual loss in children. Besides the well-known vascular abnormality, retinal dysfunction has also been reported even after ROP has resolved. We previously showed that deficiency of aldose reductase (AR), the rate-limiting enzyme in the polyol pathway, protected neonatal vasculature. Here, we further investigated the effects of AR deficiency on various retinal neurons using the mouse model of oxygen-induced retinopathy (OIR), a well-established model of ROP. METHOD: Seven-day-old mouse pups were exposed to 75% oxygen for 5 days and then returned to room air. Vascular obliteration was analyzed on isolectin-stained retinal flat-mounts. Immunohistochemistry for calbindin (horizontal cell marker), PKCα (rod bipolar cell marker), calretinin (amacrine cell marker), Tuj1 (retinal ganglion cell marker), glial fibrillary acidic protein (GFAP), nitrotyrosine (NT), and poly(ADP-ribose) (PAR) was performed on retinal sections. The results were compared between wild-type (WT) and AR-deficient (AR-/-) retinae on P14 and P17 (P, postnatal). RESULTS: On P14, calbindin and calretinin immunoreactivity was decreased in WT OIR retinae while PKCα immunoreactivity was significantly increased in AR-/- OIR retinae. But no significant differences were found for Tuj1. Yet, more intense GFAP immunoreactivity in Müller cell processes was observed in AR-/- OIR retinae. Increased NT and nuclear PAR immunoreactivity were found in WT OIR retinae but not in AR-/- OIR retinae. On P17, calbindin immunoreactivity was decreased in WT OIR retinae while PKCα-positive cell bodies appeared to be less prominent in AR-/- OIR retinae. Markedly reduced calretinin immunoreactivity, seriously distorted three strata in IPL and decreased cell bodies in INL were observed in central retinal area in WT OIR retinae but not in AR-/- OIR retinae. Again, no significant differences were found in Tuj1 immunoreactivity. GFAP immunoreactivity was significantly increased in WT OIR retinae. Importantly, significantly reduced NT and nuclear PAR immunoreactivity were observed in AR-/- OIR retinae. CONCLUSION: Our results not only demonstrated the retinal neuronal changes in the mouse model of OIR, but also showed that these changes appeared to be prominent in central avascular area, indicating a link between vascular abnormality and neuronal changes. In addition, AR deficiency provides protection in retinal neurons possibly by modulating glial responses and reducing oxidative stress, suggesting a therapeutic potential of AR inhibition in the treatment of ROP with beneficial effects on retinal neurons.