Biliverdin Reductase A Protects Lens Epithelial Cells against Oxidative Damage and Cellular Senescence in Age-Related Cataract

Abstract

Age-related cataract (ARC) is the common cause of blindness globally. Reactive oxygen species (ROS), one of the greatest contributors to aging process, leads to oxidative damage and senescence of lens epithelial cells (LECs), which are involved in the pathogenesis of ARC. Biliverdin reductase A (BVRA) has ROS-scavenging ability by converting biliverdin (BV) into bilirubin (BR). However, little is known about the protective effect of BVRA against ARC. In the present study, we measured the expression level of BVRA and BR generation in human samples. Then, the antioxidative property of BVRA was compared between the young and senescent LECs upon stress condition. In addition, we evaluated the effect of BVRA on attenuating H2O2-induced premature senescence in LECs. The results showed that the mRNA expression level of BVRA and BR concentration were decreased in both LECs and lens cortex of age-related nuclear cataract. Using the RNA interference technique, we found that BVRA defends LECs against oxidative stress via (i) restoring mitochondrial dysfunction in a BR-dependent manner, (ii) inducing heme oxygenase-1 (HO-1) expression directly, and (iii) promoting phosphorylation of ERK1/2 and nuclear delivery of nuclear factor erythroid 2-related factor 2 (Nrf2). Intriguingly, the antioxidative effect of BVRA was diminished along with the reduced BR concentration and repressed nuclear translocation of BVRA and Nrf2 in senescent LECs, which would be resulted from the decreased BVRA activity and impaired nucleocytoplasmic trafficking. Eventually, we confirmed that BVRA accelerates the G1 phase transition and prevents against H2O2-induced premature senescence in LECs. In summary, BVRA protects LECs against oxidative stress and cellular senescence in ARC by converting BV into BR, inducing HO-1 expression, and activating the ERK/Nrf2 pathway. This trial is registered with ChiCTR2000036059.

Gold Nanoparticles Encapsulated Resveratrol as an Anti-Aging Agent to Delay Cataract Development

“…Oxidative stress leads to the extreme rise of reactive oxygen species (ROS), which can accelerate cell aging and damage DNA, RNA, and proteins [ 14 ]. Cellular senescence, a cell fate that entails essentially irreversible replicative arrest, is a leading cause of cataracts [ 15 ]. Senescence induced by UV radiation, oxidation, and truncation cause the most common modifications in lens proteins, affecting cataract formation.…”

Endothelial senescence in vascular diseases: current understanding and future opportunities in senotherapeutics

“…It has been reported that a set of genes associated with NCT—as well as genes associated with the machinery responsible for transport of mRNA, the transcription-export (TREX) complex—is downregulated in various types of senescence, including endothelial senescence 196 , 197 . A recent study showed that senescent lens epithelial cells showed concomitant downregulation of a group of NCT genes and failure of the nuclear translocation of BLVRA and NRF2 198 , suggesting a possible role for NCT in the impaired delivery of these two proteins. A recent study into the disruption of the NCT machinery in fibroblasts revealed a phenotype resembling replicative senescence, indicating that several potential senescence drivers in the NCT may be leveraged for senescence therapy 199 .…”

Ubiquitination of Ku70 by Parkin promotes apoptosis of lens epithelial cells

“…Evidence has demonstrated that oxidative stress-induced apoptosis in lens epithelial cells (LECs) contributes to lens opacity [3]. Antioxidants treatment can protect LECs from apoptosis [4,5] and evidently delays H 2 O 2 -induced lens opacity [6]. In addition, oxidative stress modulates gene expression of downstream DNA repair-related targets [7].…”