title: AGEs in human lens capsule promote the TGFβ2-mediated EMT of lens epithelial cells: implications for age-associated fibrosis.
abstract: Proteins in basement membrane (BM) are long-lived and accumulate chemical modifications during aging; advanced glycation endproduct (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. We found 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 α-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.
authors: Department of Ophthalmology & Visual Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.|Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO, USA.
authors: Cibin T
authors: CT
authors: Raghavan
authors: Institute of Chemistry, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
authors: Mareen
authors: M
authors: Smuda
authors: School of Biological Sciences, University of East Anglia, Norwich, UK.
authors: Andrew J O
authors: AJ
authors: Smith
authors: Visual Sciences Research Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors: Scott
authors: S
authors: Howell
authors: Visual Sciences Research Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors: Dawn G
authors: DG
authors: Smith
authors: University Hospitals Eye Institute, Cleveland, OH, USA.
authors: Annapurna
authors: A
authors: Singh
authors: University Hospitals Eye Institute, Cleveland, OH, USA.
authors: Pankaj
authors: P
authors: Gupta
authors: Institute of Chemistry, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
authors: Marcus A
authors: MA
authors: Glomb
authors: School of Biological Sciences, University of East Anglia, Norwich, UK.
authors: Ian Michael
authors: IM
authors: Wormstone
authors: Department of Ophthalmology & Visual Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.|Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO, USA.
authors: Ram H
authors: RH
authors: Nagaraj
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D000375:Aging / Q000473:pathology*; D001485:Basement Membrane / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002386:Cataract / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis / Q000473:pathology*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007903:Lens Capsule, Crystalline / Q000378:metabolism* / Q000473:pathology*; D013058:Mass Spectrometry; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D015415:Biomarkers; D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; C509041:TGFB2 protein, human; D053781:Transforming Growth Factor beta2
keywords: advanced glycation endproducts; basement membrane; epithelial-to-mesenchymal transition; fibrosis; lens epithelial cells; posterior capsular opacification