Hesperetin protects against H2O2-triggered oxidative damage via upregulation of the Keap1-Nrf2/HO-1 signal pathway in ARPE-19 cells

Age-related macular degeneration (AMD) is an irreversible vision loss disease that primarily results from oxidative stress that causes oxidative damage to the retinal pigment epithelial (RPE) cells. Hesperetin (Hesp) is a common flavanone glycoside compound that has been demonstrated to exhibit a variety of biological and pharmacological properties that include anti-inflammatory and antioxidant properties. The aim of this study is to explore the ability of Hesp to attenuate oxidative damage in hydrogen peroxide (H2O2)-stimulated ARPE-19 cells. The results indicated that Hesp treatment not only increased cell survival but also decreased reactive oxygen species (ROS) generation, whereas these roles were effectively enhanced the superoxide dismutase (SOD) and glutathione (GSH) levels, and reduced malondialdehyde (MDA) formation. Importantly, the level of heme oxygenase-1 (HO-1) expression was increased by Hesp exposure, which resulted in a decrease after the transfection of cells with Nrf2-siRNA. Additionally, further results revealed that Hesp treatment significantly elevated Keap-1 protein expression, Nrf2 nuclear translocation and ARE activities. These observations indicated that Hesp treatment effectively protected against H2O2-induced oxidative damage in ARPE-19 cells by inhibiting cell apoptosis, ROS overproduction and MDA formation as well as enhancing the SOD and GSH levels. The underlying mechanisms may be related to the activation of the Keap1-Nrf2/HO-1 signal pathway, which may provide biological evidence to further encourage the investigation of the protective effect of Hesp in AMD disease.

Scheme summarizing the amelioration of H2O2-induced RPE cells injury by Hesp via the upregulation of Keap1-Nrf2/HO-1 signal pathway. It was known that H2O2 can result in ROS accumulation triggering oxidative stress in RPE cells and further inducing cell apoptosis and necrosis, which is closely associated with the progress and development of AMD. Importantly, Hesp could enhance the nuclear distribution of Nrf2 protein and upregulate the HO-1 protein expression, which could reduce ROS production and even alleviate RPE cells damage. (Snpp, tin protoporphyrin IX: a HO-1 inhibitor)149