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Yunpeng Du, Megan Cramer, Krzysztof Palczewski, Timothy Kern; Contribution of GPCRs and NADPH oxidase to increased generation of superoxide by retinal photoreceptor cells in elevated glucose. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6345.
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Oxidative stress is believed to play a significant role in the development of diabetic retinopathy, and we have found that the oxidative stress in diabetes is especially pronounced in photoreceptors. We are investigating the mechanisms by which elevated glucose increases generation of the superoxide anion by photoreceptors. These studies focused initially on the contribution of NADPH oxidase and its activation by GPCR-activated pathways.
Initial studies are conducted in vitro using 661W cells (derived from photoreceptors) as a test system. Superoxide release was assayed using luciginen at normal (5mM) and high (30 mM) glucose.
Incubation of the cells in 30mM glucose for 4 days resulted in a significant increase in superoxide generation. Pharmacologic inhibition of the alpha-1 adrenergic receptor with Doxazosin, phospholipase C with U73122, Ca2+ release with the membrane permeable inhibitor of IP3-induced Ca2+ release (2-aminoethyl diphenylborinate), or NADPH oxidase with apocynin each significantly inhibited the increase in superoxide production caused by elevated glucose.
These findings suggest that the induction of superoxide generation by photoreceptors in elevated glucose could be mediated through a signaling cascade involving GPCRs, PLC/IP3/Ca2+ signaling, and NADPH oxidase.
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