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AGE-RAGE interaction in the TGFβ2-mediated epithelial to mesenchymal transition of human lens epithelial cells

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An Erratum to this article was published on 02 August 2016

Abstract

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.

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Abbreviations

AGEs:

advanced glycation endproducts

BM:

basement membrane

BME:

basement membrane extract

EMT:

epithelial to mesenchymal transition

FBS:

fetal bovine serum

MEM:

minimum essential medium

PCO:

posterior capsule opacification

RAGE:

receptor for advanced glycation endproducts

ROS:

reactive oxygen species

αSMA:

alpha smooth muscle actin

CTGF:

connective tissue growth factor

TGFβ2:

transforming growth factor beta2

ZO-1:

zona occuldin-1

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Acknowledgments

This work was supported by the National Institutes of Health Grants EY022061, EY023286 (to RHN). We thank Drs. Rooban Nahomi, Johanna Rankenberg and Stefan Rakete for critical reading of the manuscript.

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  1. Department of Ophthalmology, University of Colorado School of Medicine, 12800 East 19th Avenue, RC-1 North 5102, Aurora, CO, 80045, USA

    Cibin T. Raghavan & Ram H. Nagaraj

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  1. Cibin T. Raghavan
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Correspondence to Ram H. Nagaraj.

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Raghavan, C.T., Nagaraj, R.H. AGE-RAGE interaction in the TGFβ2-mediated epithelial to mesenchymal transition of human lens epithelial cells. Glycoconj J 33, 631–643 (2016). https://doi.org/10.1007/s10719-016-9686-y

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