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A.W. Stitt, T.A. Gardiner, K.A. Stevenson, P. Humphries, D.A. C. Simpson, T.E. de Gooyer; Retinopathy Is Reduced During Experimental Diabetes in a Mouse Model of Retinitis Pigmentosa . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2577.
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Diabetic patients who also have retinitis pigmentosa (RP) may develop fewer and less severe retinopathic vascular lesions. According to the suggestion of Arden (Br J Ophthalmol. 2001 85:366–70), diabetic retinopathy leads to increased inner retinal hypoxia which may be exacerbated by oxygen usage during the dark adaptation response. Therefore RP patients with depleted rod photoreceptors may encounter proportionately less retinal hypoxia. We have tested this hypothesis using rhodopsin knockout mice (Rho–/–) as an RP model in which the diabetic milieu is superimposed. We investigated whether degeneration of the outer retina has any impact on defined gene expression responses and lesions of diabetic retinopathy.
Experimental diabetes (streptozotocin) was induced in male C57Bl6 (WT) and Rho–/– mice at 1 month and maintained for 5 months. The extent of diabetes was confirmed by measurement of glycated haemoglobin (%GHb). Retinal hypoxia was assessed using the bio–reductive drug pimonidazole (Hypoxyprobe). The retinal microvasculature was assessed by ADPase reaction and the outer retina evaluated histologically in paraffin sections. Retinal gene expression of HIF–1α, VEGF–A and TNF–α were quantified using real time RT–PCR.
%GHb was significantly increased with diabetes (p=0.0001) and was not different between strains. Hypoxia was increased in the retina of WT diabetic animals when compared to controls but this diabetes–induced change was absent in Rho –/– mice. Retinal gene expression of VEGF–A and HIF–1α were significantly increased in WT mice with diabetes (p=0.0001; p=0.001), but were unchanged in Rho–/– mice (p=0.057; p=0.487). TNF–α gene expression was significantly increased 4.9 fold in WT mice with diabetes (p=0.0009), and was also significantly increased in Rho–/– mice (p=0.026) but to a reduced extent (1.5 fold). The outer nuclear layer in non–diabetic Rho –/– mice was reduced to a single layer after 6 months, however there was significantly less degeneration of photoreceptors (P=0.001) in diabetic mice. While retinal vessels were attenuated in all Rho–/– mice, arteriolar branching defects and capillary loss were largely evident in WT but not Rho–/– diabetics.
This study suggests that loss of the outer retina reduces severity of diabetic retinopathy in a murine model. Oxygen usage by the photoreceptors during dark adaptation may contribute to retinal hypoxia and exacerbate progression of diabetic retinopathy.
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