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M. Bartoli, M. Labazi, F. Lamoke, D. Marcus; Hyperglycemia-Induced Inhibition of Thioredoxin Reductase Expression and Activity Correlates With Decreased Nrf2/ARE-Dependent Gene Expression. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5197.
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We have previously shown that increased oxidative stress in the diabetic retina correlates with decreased activity of the endogenous antioxidant system of the thioredoxin (TrxS). This effect was associated with increased expression of the thioredoxin-1 but also of its inhibitor TXNIP. Here we further analyzed the TrxS by looking at the expression and activity of its activator, thioredoxin reductase 1 (TrxR1).
We determined TrxR1 expression and activity in retinas of streptozotocin-induced diabetic rats (STZ-rat), at 2 and 4 weeks of hyperglycemia, and of age-matched normoglycemic rats. TrxR1 protein levels were measured by Western blotting analysis and TrxR1 activity was determined by using a commercially available kit assay (Cayman).
After 2 and 4 weeks of hyperglycemia, TrxR1 activity was unchanged or slightly reduced and this correlated with its protein levels, which were also unchanged in response to hyperglycemia - induced oxidative stress. TrxR1 expression is dependent on the activation of the Nrf2/ARE pathway. We, therefore, determined the expression levels of glutathione-S-transferase-1 (GST-1) and hemoxygenase-1 (HO-1) which are also primarily regulated by the Nrf2/ARE pathway. We found that GST-1 and HO-1 expression were decreased or unchanged (respectively) in response to hyperglycemia.
Our data suggest that increased oxidative stress in the diabetic retina may be caused by dysfunction of the TrxS. This appears to be the result of inhibited response of the Nrf2/ARE-dependent gene expression which includes that of TrxR1.
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