AGE-RAGE interaction in the TGFβ2-mediated epithelial to mesenchymal transition of human lens epithelial cells.
Basement membrane (BM) proteins accumulate chemical modifications with age. One such modification is glycation, which results in the formation of advanced glycation endproducts (AGEs). In a previous study, we reported that AGEs in the human lens capsule (BM) promote the TGFβ2-mediated epithelial-to-mesenchymal transition (EMT) of lens epithelial cells, which we proposed as a mechanism for posterior capsule opacification (PCO) or secondary cataract formation. In this study, we investigated the role of a receptor for AGEs (RAGE) in the TGFβ2-mediated EMT in a human lens epithelial cell line (FHL124). RAGE was present in FHL124 cells, and its 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 or EN-RAGE (an endogenous ligand for RAGE) resulted in a significant reduction in the TGFβ2-mediated EMT response. This was accompanied by a reduction in TGFβ2-mediated Smad signaling and ROS generation. These results imply that the interaction of matrix AGEs 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-associated fibrosis.
Department of Ophthalmology, University of Colorado School of Medicine, 12800 East 19th Avenue, RC-1 North 5102, Aurora, CO, 80045, USA.
Cibin T
CT
Raghavan
Department of Ophthalmology, University of Colorado School of Medicine, 12800 East 19th Avenue, RC-1 North 5102, Aurora, CO, 80045, USA. ram.nagaraj@ucdenver.edu.
Ram H
RH
Nagaraj
D058442:Capsule Opacification / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007908:Lens, Crystalline / Q000378:metabolism* / Q000473:pathology; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*
C000593871:AGER protein, human; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; C509041:TGFB2 protein, human; D053781:Transforming Growth Factor beta2
AGEs; Basement membrane; EN-RAGE; Epithelial to mesenchymal transition; Posterior capsule opacification; RAGE