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T. J. Giove, M. M. Desphande, J. Blom, J. P. Flannery, C. Imes, W. D. Eldred; Early Neuronal Changes in the Diabetic Retina Are Accompanied by a Modulation in Nos Function. Invest. Ophthalmol. Vis. Sci. 2008;49(13):174. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy (DR) is one of the leading causes of blindness in the developed world. Most of the research on DR has focused on the vascular complications that lead to retinal ischemia and eventual cell death. While this is an important aspect of DR, the early neuronal complications that result from this metabolic disorder have been largely overlooked. In the present study we examine these neuronal complications and the involvement of nitric oxide (NO).
We used a combination of immunocytochemistry, western blots, qPCR, and NO imaging to analyze control and diabetic mouse retinas.
We confirm previous work that has shown aberrant ERGs in mice with STZ induced diabetes after 5 weeks, before conventional vascular complications are thought to begin. We find changes in several neural markers using immunocytochemistry such as calbindin and neuronal microfilaments, as well as indications of apoptosis as assayed by changes in apoptotic genes Mcl-1 and Bak. These changes are seen before any change in VEGF levels. Nitric oxide (NO) is an important signaling molecule in the retina which is also implicated in diabetic retinopathy due to its potential to act as a reactive oxidative species. We show a decrease in neuronal nitric oxide synthase (nNOS) using immunocytochemistry that is not reversible by insulin. Real-time quantitative PCR analysis of nNOS shows no change in levels of nNOS message. Real-time NO imaging using DAF-FM, however shows a clear increase in NOS activity with a pattern that closely matches that of nNOS and this increase is reversible by application of insulin or pharmacological inhibition of NOS.
Taken together, these data suggest that nNOS activity may be regulated at the protein level in the diabetic retina. This increase in NOS activity and NO production in the diabetic retina may contribute to the neuronal dysfunction seen prior to the vascular pathology.
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