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Nrf2 protects against methamphetamine-induced nephrotoxicity by mitigating oxidative stress and autophagy in mice
Wenjuan Dong1, Jia Wan2, Hao Yu3
1NHC Key Laboratory of Drug Addiction Medicine, School of Forensic Medicine, Kunming Medical University, Kunming 650500, China.
Abstract:
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.
Insights
Nuclear factor erythroid 2-related factor 2 (Nrf2) protects against methamphetamine-induced kidney damage by reducing oxidative stress and autophagy. Nrf2 activation alleviates injury, while its deficiency exacerbates it.
Area of Science:
- Toxicology
- Molecular Biology
- Nephrology
Background:
- Methamphetamine (MA) abuse is a significant cause of kidney damage.
- The precise molecular mechanisms underlying MA-induced nephrotoxicity are not fully understood.
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical regulator of cellular defense against stress.
Purpose of the Study:
- To investigate the role of Nrf2 in the pathogenesis of MA-induced renal injury.
- To determine if Nrf2 activation can protect against MA nephrotoxicity.
- To elucidate the impact of Nrf2 deficiency on MA-induced kidney damage.
Main Methods:
- Established a mouse model of MA-induced nephrotoxicity.
- Utilized pharmacological Nrf2 activation and genetic Nrf2 knockout models.
- Assessed kidney function biomarkers, histopathological changes, oxidative stress markers, and autophagy-related factors (LC3, Beclin 1).
Main Results:
- MA exposure caused significant kidney damage, increased renal dysfunction biomarkers, oxidative stress, and autophagy.
- Pharmacological activation of Nrf2 attenuated MA-induced kidney injury, reducing oxidative stress and autophagy.
- Nrf2 knockout mice exhibited exacerbated MA-induced nephrotoxicity, with increased kidney injury molecule-1 (KIM-1) expression, oxidative stress, and autophagy.
Conclusions:
- Nrf2 plays a protective role against methamphetamine-induced nephrotoxicity.
- Nrf2 mitigates MA-induced kidney damage by suppressing oxidative stress and autophagy.
- Targeting Nrf2 may represent a therapeutic strategy for methamphetamine-related kidney injury.
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