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Meihua He, Hong Pan, Chunxia Xiao, Mingliang Pu; NADPH oxidase 4-derived Reactive Oxygen Species Mediate the Activation of Adaptive Antioxidant Pathways in Early Diabetic Retinas of db/db mice. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2436. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the oxidative status and the role of Nox4 in the regulation of Nrf2-mediated antioxidant pathway in the retina of db/db mice.
Male db/db C57BLKS/J mice aged at 8, 12, and 20 wks were used in this study. Age-matched male heterozygous db/m littermates were used as control. Animals were enucleated and isolated retinas were prepared for reactive oxygen species (ROS) detection, immunohistochemistry, and western blotting analysis. ROS generation was detected by dihydroethidium (DHE) assay, the expression of 4-hydroxy-2-nonenal (HNE), NADPH oxdase-4 (Nox4), and heme oxygenase-1 (HO-1) were examined by immunohistochemistry and western blotting.
ROS generation in the retinas of db/db mice increased at 8 wks and continued to progress at 20 wks of ages, compared to age-matched db/m mice. Similarly, the expression of HNE, an end-product of polyunsaturated fatty acid oxidation,was also increased in the retina of db/db mice in all three age groups (8, 12, and 20 wks). However, the increased expression of Nox4 was only observed in the retinas of 8 and 12 wks, but not 20 wks db/db mice compared to age-matched db/m mice. Meanwhile, in comparison with age-matched db/m mice, the expression of HO-1, an Nrf2-mediated antioxidant, was also increased in the retinas of db/db mice aged at 8 and 12 wks, but not at 20 wks.
The present results suggest that oxidative stress occurs in the early stages of diabetic retina and Nox 4 contributes to the increased oxidative stress (before 20 wks). Nrf2-mediated adaptive antioxidant pathway was activated to counteract the increased oxidative stress in early diabetic retinas. The similar activation pattern of Nox4 and HO-1 suggests that Nox4-derived ROS may play an important role in regulating the activation of Nrf2-mediated antioxidant pathway during the early stages of diabetic retinopathy in db/db mice.
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