Research Paper Volume 11, Issue 9 pp 2699—2723

Laminin α4 overexpression in the anterior lens capsule may contribute to the senescence of human lens epithelial cells in age-related cataract

Yu Yan 1, 2, , Haiyang Yu 1, 2, , Liyao Sun 1, 2, , Hanruo Liu 3, , Chao Wang 1, 2, , Xi Wei 1, 2, , Fanqian Song 1, 2, , Hulun Li 4, , Hongyan Ge 1, , Hua Qian 2, , Xiaoguang Li 2, , Xianling Tang 1, , Ping Liu 1, ,

  • 1 Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, 150001, China
  • 2 Department of Pharmacology, College of Pharmacy, Harbin Medical University, and Heilongjiang Academy of Medical Sciences, Harbin, 150081, China
  • 3 Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Science Key Lab, Beijing, 100000, China
  • 4 Department of Neurobiology, Neurobiology Key Laboratory, Harbin Medical University, Harbin, 150081, China

received: November 6, 2018 ; accepted: April 27, 2019 ; published: May 10, 2019 ;

https://doi.org/10.18632/aging.101943
How to Cite

Copyright: Yan et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Senescence is a leading cause of age-related cataract (ARC). The current study indicated that the senescence-associated protein, p53, total laminin (LM), LMα4, and transforming growth factor-beta1 (TGF-β1) in the cataractous anterior lens capsules (ALCs) increase with the grades of ARC. In cataractous ALCs, patient age, total LM, LMα4, TGF-β1, were all positively correlated with p53. In lens epithelial cell (HLE B-3) senescence models, matrix metalloproteinase-9 (MMP-9) alleviated senescence by decreasing the expression of total LM and LMα4; TGF-β1 induced senescence by increasing the expression of total LM and LMα4. Furthermore, MMP-9 silencing increased p-p38 and LMα4 expression; anti-LMα4 globular domain antibody alleviated senescence by decreasing the expression of p-p38 and LMα4; pharmacological inhibition of p38 MAPK signaling alleviated senescence by decreasing the expression of LMα4. Finally, in cataractous ALCs, positive correlations were found between LMα4 and total LM, as well as between LMα4 and TGF-β1. Taken together, our results implied that the elevated LMα4, which was possibly caused by the decreased MMP-9, increased TGF-β1 and activated p38 MAPK signaling during senescence, leading to the development of ARC. LMα4 and its regulatory factors show potential as targets for drug development for prevention and treatment of ARC.

Abbreviations

HE staining: hematoxylin-eosin staining; IHC: immunohistochemical staining; IP: immunoprecipitation; mAbs: monoclonal antibodies; pAbs: polyclonal antibodies; IB: immunoblotting; SA-β-gal staining: senescence-associated β-galactosidase staining; IF: immunofluorescence; H2O2: hydrogen peroxide; ALC: anterior lens capsule; LECs: lens epithelial cells; BM: basement membrane; LM: laminin; TGF-β1: transforming growth factor-beta1; MMP-9: matrix metalloproteinase-9; GLB1: lysosomal β-galactosidase; ARC: age-related cataract.