Nrf2 protects against methamphetamine-induced nephrotoxicity by mitigating oxidative stress and autophagy in mice.

Methamphetamine (MA) is a widely abused drug that can cause kidney damage. However, the molecular mechanism remains unclear. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that regulates resistance to oxidative and proteotoxic stress. In this study, we investigated the role of Nrf2 in MA-induced renal injury in mice. Nrf2 was pharmacologically activated and genetically knocked-out in mice. The animal model of MA-induced nephrotoxicity was established by injecting MA (2 mg/kg) intraperitoneally twice a day for 5 days. Histopathological alterations were shown in the MA-exposed kidneys. MA significantly increased renal function biomarkers and kidney injury molecule-1 (KIM-1) levels. MA decreased superoxide dismutase activity and increased malondialdehyde levels. Autophagy-related factors (LC3 and Beclin 1) were elevated in MA-treated mice. Furthermore, Nrf2 increased in the MA-exposed kidneys. Activation of Nrf2 may attenuate histopathological changes in the kidneys of MA-treated mice. Pre-administration of Nrf2 agonist significantly decreased KIM-1 expression, oxidative stress, and autophagy in the kidneys after MA toxicity. In contrast, Nrf2 knockout mice treated with MA lost renal tubular morphology. Nrf2 deficiency increased KIM-1 expression, oxidative stress, and autophagy in the MA-exposed kidneys. Our results demonstrate that Nrf2 may protect against MA-induced nephrotoxicity by mitigating oxidative stress and autophagy.