High sugar-induced repression of antioxidant and anti-apoptotic genes in lens: reversal by pyruvate.

Impairment of vision in diabetes has been suggested to be due to an acceleration of the polyol pathway in the lens as well as in the retina. This acceleration is attributed largely to the rate-limiting steps of glycolysis and consequent diversion of glucose in the polyol pathway with its consequent effects on diverse tissue transport and redox activities. In addition, high sugar also induces a generalized oxidative stress via generating superoxide and its derivatization to other reactive oxygen species (ROS). While the immediate toxicity of hyperglycemia could be linked to the acceleration of this pathway, we hypothesize that in the long term, the toxic effects of the high sugar level are due to an upregulation of certain microRNAs (as we have shown before) and consequent repression of the transcription and translation of many antioxidant and anti-apoptotic genes. Therefore, in the present study, we measured the expression levels of certain major antioxidant and pro- and anti-apoptotic mRNAs in the lenses of mice made hyperglycemic by feeding a high galactose diet, without or with fortification with 1% sodium pyruvate-a potent ROS scavenger. As speculated, the expression of several antioxidant and anti-apoptotic mRNAs has been found to be significantly repressed in the lenses of animals fed a high galactose diet. Such repression was significantly prevented by pyruvate. Thus, the findings also strongly suggest that visual impairment induced by the diabetic hyperglycemia could be treatable by administration of certain anti-microRNAs.