Inhibition of histone deacetylase protects the damaged cataract via regulating the NF-κB pathway in cultured lens epithelial cells

Abstract

Induction of oxidative damage by the activation of histone deacetylase (HDAC) is an integral event that causes major membrane damage of ocular tissues and leads to the pathogenesis of cataract. It is elucidated that nuclear factor-κB is a mediator in the process of cataract development. However, studies on the role played by epigenetic proteins in regulating cataract pathogenesis are limited. Hence, in the current investigation, ARPE-19 human retinal epithelial cells were used as an experimental model to elucidate the role of HDAC inhibition and its mechanism behind the cataract pathogenesis. ARPE-19 cells were exposed to H2O2, with and without Trichostatin A (TSA), a pan-HDAC inhibitor, and maintained along with control cells without any treatment. On exposure to H2O2, cells were susceptible to oxidative stress as it is evident from the reduced expression levels of superoxide dismutase (SOD), catalase, and GSH levels. Simultaneously, H2O2-exposed cells showed the nuclear translocation of NF-κB with the activation of inflammatory cytokines such as CXCL1 and IL-6. In addition, the mRNA expression analysis revealed that the GADD45α, COX-2, MCP-1, and ICAM-1 expressions were increased in H2O2 group. Moreover, the activity of HDAC was increased to 2-fold with a significant reduction in the histone acetyltransferase (HAT) activity in cells that were maintained under oxidative conditions. However, TSA was able to inhibit the critical cytokines’ expression with attenuated HDAC activity and limited NF-κB translocation. Furthermore, pre-treatment of TSA significantly suppressed the transcript levels of up-regulated inflammatory markers in cells. Together, these findings offer new insight into the role of HDACs in regulating cellular processes involved in the pathogenesis of cataract as well as the potential use of HDAC inhibitors as therapeutics for controlling the disease progression.