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Investigations into ferroptosis in methylmercury-induced acute kidney injury in mice
Yingrong Ye1, Yichun Chen1, Hanpeng Wu1
1College of Life Sciences and Engineering, Foshan University, Foshan, Guangdong Province, People's Republic of China.
Abstract:
Methylmercury (MeHg) is a highly poisonous form of mercury and a risk factor for kidney impairment in humans that currently has no effective means of therapy. Ferroptosis is a non-apoptotic metabolic cell death linked to numerous diseases. It is currently unknown whether ferroptosis takes part in MeHg-induced kidney damage. Here, we established a model of acute kidney injury (AKI) in mice by gavage with different doses of MeHg (0, 40, 80, 160 μmol/kg). Serological analysis revealed elevated levels of UA, UREA, and CREA; H&E staining showed variable degrees of renal tubule injury; qRT-PCR detection displayed increased expression of KIM-1 and NGAL in the groups with MeHg treatment, indicated that MeHg successfully induced AKI. Furthermore, MDA levels enhanced in renal tissues of mice with MeHg exposure whereas GSH levels decreased; ACSL4 and PTGS2 nucleic acid levels elevated while SLC7A11 levels reduced; transmission electron microscopy illustrated that the density of the mitochondrial membrane thickened and the ridge reduced considerably; protein levels for 4HNE and TfR1 improved since GPX4 levels declined, all these results implying the involvement of ferroptosis as a result of MeHg exposure. Additionally, the observed elevation in the protein levels of NLRP3, p-p65, p-p38, p-ERK1/2, and KEAP1 in tandem with downregulated Nrf2 expression levels indicate the involvement of the NF-κB/NLRP3/MAPK/Nrf2 pathways. All the above findings suggested that ferroptosis and the NF-κB/NLRP3/MAPK/Nrf2 pathways are implicated in MeHg-induced AKI, thereby providing a theoretical foundation and reference for future investigations into the prevention and treatment of MeHg-induced kidney injury.
Insights
Methylmercury (MeHg) exposure induces kidney damage by promoting ferroptosis, a form of cell death. This study reveals MeHg-induced acute kidney injury (AKI) involves ferroptosis and specific molecular pathways, offering targets for future therapies.
Area of Science:
- Toxicology
- Cell Biology
- Nephrology
Background:
- Methylmercury (MeHg) is a potent neurotoxin and a risk factor for kidney impairment.
- Ferroptosis, a regulated cell death pathway, is implicated in various diseases.
- The role of ferroptosis in MeHg-induced kidney injury remains unclear.
Purpose of the Study:
- To investigate the involvement of ferroptosis in methylmercury-induced acute kidney injury (AKI).
- To elucidate the underlying molecular mechanisms, including specific signaling pathways.
Main Methods:
- Acute kidney injury (AKI) was induced in mice using methylmercury (MeHg) via oral gavage.
- Biochemical analyses (serum markers, oxidative stress indicators), histological examination (H&E staining), gene expression (qRT-PCR), and transmission electron microscopy were performed.
- Protein levels of key molecules in ferroptosis and signaling pathways were assessed.
Main Results:
- MeHg exposure successfully induced AKI in mice, evidenced by elevated serum creatinine and urea, renal tubule injury, and increased KIM-1 and NGAL expression.
- MeHg exposure led to ferroptosis, indicated by increased MDA, decreased GSH, altered levels of ferroptosis-related genes (ACSL4, PTGS2, SLC7A11), mitochondrial changes, and altered protein expression (4HNE, TfR1, GPX4).
- Activation of NF-κB/NLRP3/MAPK pathways and inhibition of the Nrf2 pathway were observed, suggesting their involvement in MeHg-induced AKI.
Conclusions:
- Ferroptosis plays a significant role in methylmercury-induced acute kidney injury.
- The NF-κB/NLRP3/MAPK/Nrf2 signaling pathways are implicated in the pathogenesis of MeHg-induced kidney damage.
- These findings provide a theoretical basis for developing therapeutic strategies against MeHg-induced kidney injury.
