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

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

doi:10.18632/aging.101943

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.

Highlights

Age-related cataract (ARC), characterized by lens opacity and visual impairment in the middle-aged and elderly, is responsible for nearly half of all blindness worldwide [1]
We found that the protein levels of p53 in www.aging-us.com elderly cataractous anterior lens capsule (ALC) were elevated (Fig. 1A), in an age-dependent manner (R=0.192) (Fig. 1B), as evidenced via immunoblot analysis and Coomassie brilliant blue (CBB) staining
The objectives of this study were to determine whether ALCs senescence influences the severity of age-related cataract (ARC), as well as whether the capsular proteins, total LM, LMα4, and their possible mediators, MMP9 and transforming growth factor-beta1 (TGF-β1), played a role in such a senescence response, contributing to the development of ARC

Summary

Introduction

Age-related cataract (ARC), characterized by lens opacity and visual impairment in the middle-aged and elderly, is responsible for nearly half of all blindness worldwide [1]. Oxidative stress caused by reactive oxygen species (ROS) has long been recognized as a major mechanism www.aging-us.com by which cells are damaged and cataracts are formed [57]. Hydrogen peroxide (H2O2) is the main intracellular ROS in the aqueous humor that can cause protein oxidation and aggregation, lipid peroxidation, and DNA damage, and can decrease antioxidant levels in the lens, eventually accelerating the damage to the lens epithelial cells (LECs), resulting in subsequent cataract development [8,9,10]. Recent studies have reported that more senescent LECs were observed in the elderly ARC patients, oxidative stress induced cellular senescence may contribute to the development of ARC [15, 16]

Objectives

Methods

Results

Conclusion