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Kun-Che Chang, Mark Petrash; Aldose Reductase Inhibition Suppresses Transforming Growth Factor Beta 2 (TGF-beta 2)-induced Migration and Epithelial-to-Mesenchymal Transition of Lens-Derived Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3212.
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© ARVO (1962-2015); The Authors (2016-present)
Cataract surgery involves physical removal of lens tissue, but is associated with a high complication rate due to TGFβ-mediated epithelial-to-mesenchymal transition (EMT) of residual lens epithelial cells to produce posterior capsule opacification (PCO). In this study, we sought to determine a mechanism for how AR inhibition reduces EMT markers in lens epithelium-derived cells following exposure to TGF-β2.
AR inhibitory activity was determined using sorbitol accumulation assay. We observed cell migration using transwell and scratch assays. The correlation of AR inhibition and SMADs pathway was conducted by using Western blot. The interactions of AR and SMADs were demonstrated by co-immunoprecipitation (Co-IP) and proximity ligation assay (PLA). Epithelial-to-mesenchymal transition (EMT) expression was measured by Western blot and quantitative polymerase chain reaction (q-PCR). MMP-9 gelatinase activity was measured in conditioned medium by zymography.<!--EndFragment-->
We observed that either Sorbinil-mediated AR inhibition or siRNA-mediated AR gene knockdown prevented LECs migration following TGF-β2 exposure. AR inhibition or AR knockdown reduced SMAD2 and SMAD3 activation triggered by TGF-β2 as well as MMP-9 activation. In addition, we demonstrated AR inhibition or AR knockdown decreases TGF-β2-induced EMT responses. Co-IP studies and PLA were used to demonstrate that AR and SMAD2 interact either directly or in close concert with additional factor(s) in a non-enzymatic manner.<!--EndFragment-->
This study provides a possible mechanism for aldose reductase (AR) in lens epithelial cells (LECs) migration and epithelial-to-mesenchymal transition (EMT) during PCO. AR inhibition may prevent development of PCO by disrupting the TGF-β2/SMAD pathway.<!--EndFragment-->
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