Netrin-1 Overexpression in Oxygen-Induced Retinopathy Correlates with Breakdown of the Blood-Retina Barrier and Retinal Neovascularization

Abstract

Purposes: Recent research has shown netrin-1 to promote neovascularization. We evaluate the expression of netrin-1 during retinal neovascularization in a murine model of oxygen-induced retinopathy. Methods: C57BL/6J mice were exposed to 75 ± 5% oxygen for 5 days and returned to room air to induce retinal neovascularization. Retinal neovascularization was observed by fluorescence angiography and was quantified by counting the endothelial nuclei protruding into the vitreous cavity after hematoxylin-eosin staining. RT-PCR and Western blot analyses were used to determine retinal netrin-1 mRNA and protein levels at postnatal days (PN) 13, 15 and 17. Results: In fluorescence angiograms, irregular neovascularization and fluorescein leakage were observed surrounding the unperfused areas in the hypoxic group. The hypoxic group had, on average, 50.70 ± 4.56 neovascular nuclei protruding into the vitreous body, while similar nuclei were absent in the control group. Compared to the normoxic group, there were significant increases in both retinal netrin-1 mRNA and protein levels in the hypoxic group at PN13, PN15 and PN17. Conclusion: The netrin-1 level increases in murine retina under hypoxia and may be key in inducing retinal neovascularization.

Netrin-1, a urinary proximal tubular injury marker, is elevated early in the time course of human diabetes

“…Administration of recombinant netrin-1 or overexpression of netrin-1 improved conductance velocity of nerves and increased angiogenesis in diabetic mice [18]. More recently, diabetic retinopathy was associated with increased levels of netrin-1 in the vitreous fluid [19, 20]. Studies from our laboratory had shown that epithelial cell-derived netrin-1 may reduce albuminuria and interstitial fibrosis through suppression of inflammation and increased uptake of albumin [21].…”

Tubular injury marker netrin-1 is elevated early in experimental diabetes

“…Earlier studies suggest that administration of recombinant netrin-1 or overexpression of netrin-1 improved conductance velocity of nerves and increases angiogenesis in diabetic mice [18]. More recently, diabetic retinopathy was associated with increased levels of netrin-1 in the vitrous fluid [19;20]. However, the exact role of netrin-1 in diabetic complications is unknown.…”

Review of the mechanisms and therapeutic avenues for retinal and choroidal vascular dysfunctions in retinopathy of prematurity

“…In ROP, netrin‐1 has been reported by several studies to promote developmental and pathological angiogenesis in the retina . For instance, Tian et al.…”

“…For instance, Tian et al. showed that the expression levels of netrin‐1 were significantly upregulated during neovascular formation. They also showed that netrin‐1 not only participates in pathological angiogenesis, but can also induce retinal vascular permeability.…”