AGE-RAGE INTERACTION IN FIBROSIS OF THE EYE LENS

Abstract

Due to low turnover rate basement membrane (BM) proteins accumulate chemical modifications with age. Glycation is one such modification, which leads to the formation of advanced glycation endproducts (AGEs). The eye lens capsule is a BM secreted by lens epithelial cells. We have found age-dependent increases in AGE levels in the human lens capsule and significantly higher levels in cataractous lens capsules. We also found that AGEs in the human lens capsule promoted the TGFβ2-mediated epithelial-to-mesenchymal transition (EMT) of lens epithelial cells, and the AGE content of the capsule proteins was correlated to the synthesis of TGFβ2- mediated α-smooth muscle actin, which we proposed as a mechanism for posterior capsule opacification (PCO) or secondary cataract formation. We then investigated the role of a receptor for AGEs (RAGE) in the TGFβ2- mediated EMT in a human lens epithelial cell line. The RAGE levels were unaltered in cells cultured on either native or AGE-modified BM or upon treatment with TGFβ2. RAGE overexpression significantly enhanced the TGFβ2-mediated EMT responses in cells cultured on AGE-modified BM compared with the unmodified matrix. In contrast, treatment of cells with a RAGE antibody resulted in a significant reduction in the TGFβ2-mediated EMT response. This was accompanied by a reduction in TGFβ2-mediated Smad signaling. Our latest work showed that N enhances the TGFβ2-mediated EMT response lens epithelial cells. Together these results suggested that the interaction of matrix AGEs, possibly CML, with RAGE plays a role in the TGFβ2-mediated EMT of lens epithelial cells and suggest that the blockade of RAGE could be a strategy to prevent PCO and other age-related fibrosis.