Effects of Long-Term Exposure to Copper on the Keap1/Nrf2 Signaling Pathway and Msr-Related Redox Status in the Kidneys of Rats

The objective of the present study was to examine the effects of long-term exposure on oxidative damage, Keap1/Nrf2 signaling pathway, and Msr-related redox status in the kidneys of rats. Therefore, in this experimental study, a total of 32 CD-1 rats were randomized into 4 groups and treated with 30-, 60-, and 120-mg/kg Cu for 24 weeks. Different serum biomarkers suggestive of renal functions, pathological changes, and oxidative stress were analyzed in kidney tissues. Moreover, the levels of the Keap1/Nrf2 signaling pathway and redox status-related gene mRNA and proteins were also detected. The results indicated that Cu exposure dramatically increased the contents of creatinine and carbamide. Furthermore, histopathological alterations and mitochondrial damage in kidneys of rats of different Cu-treated groups were obviously observed. In addition, Cu exposure markedly changed the levels of glutathione, catalase, and total antioxidant capacity, and upregulated the contents of protein carbonyl, nitric oxide, and malondialdehyde. Moreover, higher levels of Cu treatments significantly increased the expression of Keap1/Nrf2 signaling pathway and redox status-related genes (NQO1, SOD-1, TRX, MsrA, MsrB1, MsrB2, MsrB3). Simultaneously, the mRNA expression levels of Nrf2, HO-1, and CAT were upregulated in rats exposed to 30- and 60-mg/kg Cu, but downregulated in the 120-mg/kg Cu group compared with the control group. Moreover, the Keap1/Nrf2 signaling pathway and redox status-related protein expression levels (HO-1, SOD-1, TRX, MsrA, MsrB1, MsrB2) were significantly increased in treated rats. In summary, it is suggested that the Keap1/Nrf2 signaling pathway and activation of Msr prevent Cu-induced nephrotoxicity and attenuate oxidative damage.