AGEs in human lens capsule promote the TGFβ2-mediated EMT of lens epithelial cells: Implications for age-associated fibrosis

Cibin Raghavan, Mareen Smuda, Andrew Smith, Scott Howell, Dawn Smith, Annapurna Singh, Pankaj Gupta, Marcus Glomb, Ian Wormstone, Ram Nagaraj

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Abstract

Proteins in basement membrane (BM) are long-lived and accumulate chemical modifications during aging; advanced glycation end-product (AGE) formation is one such modification. The human lens capsule is a BM secreted by lens epithelial cells. In this study, we have investigated the effect of aging and cataracts on the AGE levels in the human lens capsule and determined their role in the epithelial-to-mesenchymal transition (EMT) of lens epithelial cells. EMT occurs during posterior capsule opacification (PCO), also known as secondary cataract formation. Wefound age-dependent increases in several AGEs and significantly higher levels in cataractous lens capsules than in normal lens capsules measured by LC-MS/MS. The TGFβ2-mediated upregulation of the mRNA levels (by qPCR) of EMT-associated proteins was significantly enhanced in cells cultured on AGE-modified BM and human lens capsule compared with those on unmodified proteins. Such responses were also observed for TGFβ1. In the human capsular bag model of PCO, the AGE content of the capsule proteins was correlated with the synthesis of TGFβ2-mediated a-smooth muscle actin (αSMA). Taken together, our data imply that AGEs in the lens capsule promote the TGFβ2-mediated fibrosis of lens epithelial cells during PCO and suggest that AGEs in BMs could have a broader role in aging and diabetes-associated fibrosis.
Original languageEnglish
Pages (from-to)465–476
Number of pages12
JournalAging Cell
Volume15
Issue number3
Early online date8 Feb 2016
DOIs
Publication statusPublished - Jun 2016

Keywords

  • advanced glycation endproducts
  • basement membrane
  • epithelial-to-mesenchymal transition
  • fibrosis
  • lens epithelial cells
  • posterior capsular opacification

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