Impaired homeostasis and phenotypic abnormalities in Prdx6-/- mice lens epithelial cells by reactive oxygen species:: increased expression and activation of TGFβ

PRDX6, a member of the peroxiredoxins (PRDXs) family, is a key player in the removal of reactive oxygen species (ROS). Using targeted inactivation of the Prdx6 gene, we present evidence that the corresponding protein offsets the deleterious effects of ROS on lens epithelial cells (LECs) and regulates gene expression by limiting its levels. PRDX6-depleted LECs displayed phenotypic alterations and elevated alpha-smooth muscle actin and beta ig-h3 expression (markers for cataractogenesis), indistinguishable from transforming growth factor beta (TGF beta)-induced changes. Biochemical assays disclosed enhanced levels of ROS, as well as high expression and activation of TGF beta 1 in Prdx6(-/-) LECs. A CAT assay revealed transcriptional repression of lens epithelium-derived growth factor (LEDGF), HSP27, and alpha B-crystallin promoter activities in these cells. A gel mobility shift assay demonstrated the attenuation of LEDGF binding to heat shock or stress response elements present in these genes. A supply of PRDX6 to Prdx6(-/-) LECs reversed these changes. Based on the above data, we propose a rheostat role for PRDX6 in regulating gene expression by controlling the ROS level to maintain cellular homeostasis.