Hesperidin alleviates kidney injury induced by nano-copper through regulating endoplasmic reticulum stress and autophagy via AMPK-AKT/mTOR pathway in broiler chicken

Nano-copper (nanoCu), a nanoscale form of copper (Cu), has been widely applied in the animal husbandry industry. However, it is of great concern that the Cu exposure to humans and animals can cause toxic damage to multiple organs. Hesperidin (Hes), a flavonoid found in citrus fruits, has shown mitigating effects on various organ damages. In our study, we aimed to investigate the toxic effects of nanoCu exposure on the kidneys of chickens and the therapeutic efficacy of Hes in nanoCu-induced renal injury. Our results indicated that Hes could alleviate endoplasmic reticulum stress (ERS) caused by nanoCu exposure. Intriguingly, nanoCu significantly disrupted endoplasmic reticulum (ER) homeostasis, which manifested as increased levels of key proteins such as GRP78, PERK, and CHOP, as well as elevated H 2 O 2 levels. But Hes treatment exhibited an opposite trend. Furthermore, nanoCu significantly induced autophagy in renal cells, which was accompanied by the activation of the AMPK-AKT/mTOR pathway and a concurrent increase in the protein levels of ATG5, Beclin 1, LC3 Ⅱ/LC3 Ⅰ, and ULK1, along with a decrease in the level of p62. However, it can be reversed by Hes treatment. These findings suggest that Hes could mitigate ER homeostasis disruption and autophagy caused by nanoCu exposure, providing new insights into the pharmacological treatment of Hes in related health issues.