Abstract
Protein glutathionylation, defined as the formation of protein mixed disulfides (PSSG) between cysteine residues and glutathione (GSH), can lead to cell death. Glutaredoxin 1 (Grx1) is a thiol repair enzyme which catalyzes the reduction of PSSG. Therefore, Grx1 exerts strong anti-apoptotic effects by improving the redox state, especially in times of oxidative stress. However, there is currently no compound that is identified as a Grx1 activator. In this study, we identified and characterized Salvianolic acid B (Sal B), a natural compound, as a Grx1 inducer, which potently protected retinal pigment epithelial (RPE) cells from oxidative injury. Our results showed that treatment with Sal B protected primary human RPE cells from H2O2-induced cell damage. Interestingly, we found Sal B pretreatment upregulated Grx1 expression in RPE cells in a time- and dose-dependent manner. Furthermore, NF-E2-related factor 2 (Nrf2), the key transcription factor that regulates the expression of Grx1, was activated in Sal B treated RPE cells. Further investigation showed that knockdown of Grx1 by small interfering RNA (siRNA) significantly reduced the protective effects of Sal B. We conclude that Sal B protects RPE cells against H2O2-induced cell injury through Grx1 induction by activating Nrf2 pathway, thus preventing lethal accumulation of PSSG and reversing oxidative damage.
Highlights
The retinal pigment epithelium (RPE), lying between the photoreceptors and the choriocapillaris, is a monolayer of pigmented cells which plays essential roles in the retina, including maintaining the overlying photoreceptors, mediating the uptake of nutrients, ions, and water, phagocytizing the shed photoreceptor outer segment, and more
Our results suggest that Salvianolic acid B (Sal B) protected RPE cells against oxidative stress-induced injury through Glutaredoxin 1 (Grx1) induction via NF-E2-related factor 2 (Nrf2) activation
Grx1 functions to improve the redox state in the cell by increasing GSH levels and lowering protein glutathionylation levels
Summary
The retinal pigment epithelium (RPE), lying between the photoreceptors and the choriocapillaris, is a monolayer of pigmented cells which plays essential roles in the retina, including maintaining the overlying photoreceptors, mediating the uptake of nutrients, ions, and water, phagocytizing the shed photoreceptor outer segment, and more. The dried root of Salvia miltiorrhiza, has been recorded as a “superior grade” medicine in Shen-nung Pen-tsao Ching, the earliest materia medica extant in China [17] It has been widely used in many Asian countries for the treatment of cardiovascular disorders and cerebrovascular diseases for thousands of years. This herb contains a large number of active natural compounds which have been reported to have significant free radical scavenging effects and protective effects on heart and brain injuries induced by ischemia-reperfusion [18]. We demonstrated that Sal B protects RPE cells from H2O2-induced cell injury through up-regulating Grx to prevent the oxidation of critical sulfhydryl proteins
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