Aucubin alleviates diabetic nephropathy by inhibiting NF-κB activation and inducing SIRT1/SIRT3-FOXO3a signaling pathway in high-fat diet/streptozotocin-induced diabetic mice

The potential protective mechanism of Aucubin (AU) in STZ/HFD-induced diabetic nephropathy (DN). AU decreased inflammatory cytokines production by down-regulated NF-κB activation. Besides, AU ameliorates oxidative stress in kidneys of HFD/STZ-induced diabetic mice, and these effects are found at least in part through modulation of the Nrf2 and FOXO3a pathways via up-regulated SIRT1 and SIRT3 activation. [Display omitted] •AU improves renal function in high-fat diet/streptozotocin-induced diabetic mice.•AU promotes endogenous antioxidant defenses by Nrf2 and FOXO3a activation.•AU provokes FOXO3a translocation by up-regulation of SIRT1 and SIRT3 expressions.•AU attenuates the pro-inflammatory cytokines by inhibiting NF-κB signaling pathway. Oxidative stress and inflammation are two important pathological mechanisms in diabetic nephropathy (DN). Aucubin (AU), a natural iridoid glucoside, possessing remarkable anti-inflammatory and anti-oxidation activity, has been used to treat diabetic complications. However, underlying mechanism of protective action in DN remains unclear. In the present study, AU significantly alleviated albuminuria, glomerular extracellular matrix expansion, renal fibrosis, and inflammation caused by diabetes after ten weeks of treatment. Moreover, AU significantly inhibited oxidativestressmarkers in kidney tissue. In addition, we demonstrated that AU promoted endogenous antioxidant defenses by triggering Nrf2 and FOXO3a nuclear translocation, respectively, and up-regulation of antioxidant genes, including NQO1, HO-1, Mn-SOD, and CAT. These effects may be, in part, mediated by inducing SIRT1 and SIRT3 activities. Furthermore, AU also attenuated pro-inflammatory cytokines in renal tissue by inhibiting the NF-κB signaling pathway. Taken together, our results suggested that AU is a potential natural agent for the prevention of diabetes-induced DN.