Oxidative stress is believed to be a causative factor in age-related cataracts. The purpose of our research is to better understand the underlying molecular mechanisms that play a role in this prevalent lens disease. Differential display, microarray, and RT-PCR were used to measure differential gene expression in model systems of age-related cataract. Up-regulation of alpha-smooth muscle actin and beta-actin and down-regulation of matrix metalloproteinases occurred in rat lenses exposed for four hours to riboflavin and light-a system that generates superoxide and hydrogen peroxide. These changes suggest transdifferentiation and cellular restructuring of the lens prior to cataract formation. In a second system, we tested the hypothesis that lens cells up-regulate anti-oxidant defense systems in conditions of chronic oxidative stress. Gene transcripts for catalase and glutathione peroxidase were up-regulated in a lens cell line that had been conditioned for over a year to survive in 125 microM hydrogen peroxide. The enzyme activities of catalase and glutathione peroxidase were also increased. RT-PCR showed that ferritin, reticulocalbin, and alphaB-crystallin were up-regulated, while alphaA-crystallin was down-regulated and mitochondrial transcripts were unchanged. These data indicate that lens cells use detoxification enzymes as a first line of defense against chronic oxidative stress. Our studies are relevant to the hypothesis that oxidative stress causes age-related cataracts. We have shown that survival mechanisms can be up-regulated in lens cells. Since enzyme activities diminish in the aging lens, anti-oxidant therapy could prove useful.
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