Sesamin exerts protective effects against diquat-induced acute kidney injury by inhibiting oxidative stress, apoptosis and autophagy: A key role for the SIRT5/FOXO3a signaling pathway.

Diquat poisoning leads to acute kidney injury (AKI) with a high mortality rate. Sesamin possesses antioxidant, anti-inflammatory and anti-apoptotic properties. However, whether sesamin can protect against diquat-induced AKI remains unclear. This study aimed to investigate whether sesamin can exert protective effects against diquat-induced AKI and its potential molecular mechanisms. Diquat induced reactive oxygen species (ROS) generation, mitochondrial damage, apoptosis, and autophagy in human proximal tubular cells (HK-2 cells). SIRT5, a member of the sirtuin family of NAD + -dependent histone deacetylases, was slightly increased in diquat-exposed HK-2 cells. Additionally, diquat upregulated FOXO3a protein expression, accompanied by decreased acetyl-FOXO3a and enhanced nuclear translocation of FOXO3a in HK-2 cells. The toxic effects of diquat in HK-2 cells were further exacerbated by SIRT5 knockdown, but ameliorated by SIRT5 overexpression. Molecular docking and cellular thermal shift assay indicated that sesamin bound to SIRT5, with PHE70 likely serving as a key binding site. Sesamin attenuated diquat-induced ROS generation, mitochondrial damage, apoptosis, and autophagy in HK-2 cells by activating the SIRT5/FOXO3a pathway. Meanwhile, sesamin significantly attenuated diquat-induced AKI in mice by inhibiting oxidative stress, apoptosis and autophagy. Collectively, oxidative stress, apoptosis, and autophagy are involved in diquat-induced acute kidney injury. SIRT5/FOXO3a signaling pathway contributes to diquat-induced cytotoxicity in renal tubular epithelial cells. Sesamin exerts protective effects against diquat-induced acute kidney injury in mice.