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Shambhu D Varma, Krish Chandrasekaran; Repression of Antioxidant Genes in the lens by high sugar levels. Prevention by Antioxidants.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5600.
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© ARVO (1962-2015); The Authors (2016-present)
The toxic effects of high sugar levels as prevalent in the diabetic tissues including the eye is attributable to an acceleration of the polyol pathway and the formation of reactive oxygen species. We hypothesize that in the long term, the toxicity is due to an upregulation of certain microRNAs and consequent repression of antioxidant and anti-apoptotic genes. The present objective was to verify this hypothesis by determining mRNA expression in the lenses of mice rendered hyperglycemic by feeding a high galactose diet.
CD-1 mice were fed either a normal diet or the diet containing 25% Galactose without or with 1% Sodium Pyruvate. One week after, the animals were euthanized, lenses dissected out, RNA isolated, it was reverse transcribed and quantified for antioxidant and anti-apoptotic mRNAs by PCR using antioxidant (PAMM-065Z) and the anti- apoptotic (PAMM-012Z) gene arrays obtained from QIAGEN. Results are expressed as ratios of the means of 2^(-Δt Ct.) of the experimental/ 2^(-ΔCt)of the controls.
High galactose feeding downregulated the expression of several antioxidant genes such as Atr, Epx. Ercc2, GPx5, and Gpx6 etc.,. Significant inhibitions were also found in the in the translation of Mpo and Noxa1 genes. Contrarily, several pro-apoptotic genes such as Wnxa5, Atf5, Casp1, and Casp4 were upregulated. There was also a tendency towards a down regulation of anti-apoptotic genes such as the Bcl2s, Birk5, Bnip2, Gadd 45 A and nme5. It was interesting to note also that these changes were antagonized by presence of pyruvate in the galactose diet.
The results are in conformity with the hypothesis that high sugar induced pathological changes in the lens and eventual cataract formation is due to oxidative stress induced down regulation of antioxidant and upregulation of the pro-apoptotic genes in the tissue. That these effects are due to oxidative stress was strongly suggested by the inhibitory/antagonistic effect of pyruvate. The results are in agreement with the high sugar induced upregulation of microRNAs demonstrated earlier. Such upregulation is known to hybridize with the mRNAs and repress protein translation. This mode of sugar toxicity in the lens has been demonstrated for the first time.
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