Inhibition of SIRT1 promotes ultraviolet B induced cataract via downregulation of the KEAP1/NFE2L2 signaling pathway.

Due to continuous exposure to ultraviolet B(UVB) radiation, eye lenses are constantly subjected to oxidative stress that induces lens epithelial cell (LEC) apoptosis, which has been associated with the inactivation of Sirtuin1 (SIRT1). It is well-established that NFE2L2 has a major protective effect on UVB-induced oxidative stress and damage. However, whether UVB radiation affects oxidative/antioxidative imbalance and damages LECs by inactivating the protective NFE2L2-mediated antioxidative stress pathway through inhibition of SIRT1 is unknown. In our research, we established in vivo and in vitro UVB exposure models in Sprague Dawley rats and SRA01/04 cells, respectively, to investigate the effect of UVB radiation on the NFE2L2/ KEAP1 pathway and the role of SIRT1 in this process. The in vivo findings revealed that UVB radiation exposure decreased Sirt1 and Nfe2l2 levels, upregulated Keap1 expression, led to an oxidative/antioxidative imbalance and increased LEC apoptosis in the eye lens. Sirt1 downregulated Keap1 expression levels, but activated Nfe2l2 and its downstream target proteins. The in vitro findings showed that UVB inhibited the deacetylation of SIRT1 target proteins and increased the acetylation levels of KEAP1 and NFE2L2. We also found that UVB radiation exposure led to a significant decrease in both co-localization levels and protein interaction between SIRT1 and KEAP1. In addition, the inhibition of SIRT1 increased KEAP1 levels, inhibited the activity of NFE2L2 and decreased co- localization levels and protein interactions between NFE2L2 and KEAP1. These results suggested that UVB radiation decreased SIRT1 levels and inhibited the KEAP1/NFE2L2 pathway, thereby reducing its antioxidant effect, which might be an important mechanism of UVB-induced cataract. [Display omitted] • UVB caused cataracts through oxidative stress and apoptosis. • UVB induced a reduction in Sirt1 concentration both in vivo and in vitro. • UVB caused oxidative stress in lens by affecting the KEAP1/NFE2L2 pathway. • UVB regulated the expression of KEAP1/NFE2L2 signaling pathway by inhibiting Sirt1. [ABSTRACT FROM AUTHOR]