Abstract
Purpose :
Currently, there is a lack of effective therapeutic interventions for posterior capsule opacification (PCO) due to an incomplete understanding of its mechanisms. We conducted a study investigating the potential role of advanced glycation end products (AGEs) in inducing senescence in lens epithelial cells (LECs) within the lens capsule. We examined how senescent LECs may contribute to PCO development by inducing epithelial-to-mesenchymal transition (EMT) in non-senescent LECs.
Methods :
Young and aged capsules from pseudophakic cadaver eyes were isolated and measured for senescence markers in the capsule-adhering LECs using senescence-associated-beta-galactosidase stain and western blots for senescence markers. LECs were cultured on ECM or AGE-modified ECM (ECM-AGEs) for 96 h and measured for p21 and p16 expression using qPCR and western blot. ROS production was measured in cells cultured on ECM or ECM-AGEs. Cells were additionally treated with NOX4 inhibitor GKT136901 to determine if suppressing ROS downregulated senescence. Conditioned media from cells cultured on ECM or ECM-AGEs was incubated on naïve cells and EMT markers were measured. The impact of RAGE antagonist on ECM-AGE-induced EMT was investigated using western blot.
Results :
Senescent LECs were observed in the capsules of pseudophakic eyes. LECs cultured on aged lens capsules for three days underwent senescence; this effect was not seen in LECs cultured on young lens capsules. After a 28-day culture on human capsules, LECs showed an age-dependent increase in senescence, and treatment with a RAGE antagonist reduced posterior capsule wrinkling and cell growth. LECs cultured on ECM-AGEs showed a concentration-dependent increase in the expression of senescence markers and ROS levels. Inhibition of ROS production and treatment with a RAGE antagonist reduced LEC senescence. Additionally, conditioned media from ECM-AGEs-treated LECs induced EMT in naïve LECs, through TGF-β2 and IL-6.
Conclusions :
AGE-RAGE interaction induces oxidative stress, leading to the senescence of LECs, which triggers EMT in neighboring LECs and potentially contributes to the pathogenesis of PCO.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.