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Grape seed proanthocyanidin extract inhibits ferroptosis by activating Nrf2/HO-1 and protects against diabetic kidney
Tingting Li1,2, Hao Wang2, Baolei Chang2
1College of Public Health, Xinjiang Medical University, Urumqi, China.
Background:
The main pathological characteristic of diabetic kidney disease (DKD) is renal dysfunction caused by tubular injury. Ferroptosis is a recently discovered form of cell death closely linked to renal tubular injury in DKD. Nuclear factor erythroid-2 related factor 2/heme oxygenase 1(Nrf2/HO-1) is crucial in controlling ferroptosis. Grape seed proanthocyanidin extract (GSPE) mitigates renal dysfunction in DKD by activating Nrf2/HO-1 pathway. However, the role of GSPE in protecting against DKD through ferroptosis modulation has been insufficiently explored.
Methods:
Streptozotocin (STZ)-induced diabetic rat models and HK2 cells cultured with high glucose were used as experimental objects in this study. HE and PAS staining was used to observe the morphological changes of rat kidney. Fe2+ and reactive oxygen species (ROS) levels as well as apoptosis were determined by fluorescent staining. Transferrin receptor protein 1(TfR1), acylcoa synthetase long chain family member 4(ACSL4), glutathione peroxidase 4 (GPX4), Nrf2 and HO-1 proteins were detected by western blot. Subsequently, Nrf2 was knocked down and oxidative stress and ferroptosis were observed in HK2 cells.
Results:
In vivo and vitro result showed that GSPE treatment significantly lessened renal impairment, oxidative stress, and ferroptosis in DKD, while the application of Ferrostatin-1 (Fer-1) notably amplified the anti-ferroptotic effect of GSPE. Moreover, the anti-ferroptotic effect of GSPE was markedly diminished after Nrf2 expression was downregulated in HK2 cells.
Conclusion:
GSPE treatment reduced ferroptosis in DKD by modulating the Nrf2/HO-1. In conclusion, our results underscore the significance of ferroptosis in DKD and present new perspectives on the protective effects of GSPE in this condition.
Insights
Grape seed proanthocyanidin extract (GSPE) reduces kidney damage in diabetic kidney disease (DKD) by inhibiting ferroptosis. This protective effect is mediated through the Nrf2/HO-1 pathway, highlighting GSPE as a potential therapeutic agent for DKD.
Area of Science:
- Nephrology
- Cell Biology
- Pharmacology
Background:
- Diabetic kidney disease (DKD) is characterized by renal dysfunction due to tubular injury.
- Ferroptosis, a distinct cell death pathway, is implicated in DKD-related tubular injury.
- The Nuclear factor erythroid-2 related factor 2/heme oxygenase 1 (Nrf2/HO-1) pathway plays a key role in regulating ferroptosis.
Purpose of the Study:
- To investigate the protective effects of Grape seed proanthocyanidin extract (GSPE) against ferroptosis in diabetic kidney disease (DKD).
- To elucidate the role of the Nrf2/HO-1 pathway in GSPE's protective mechanism against DKD.
Main Methods:
- Established streptozotocin (STZ)-induced diabetic rat models and high glucose-cultured HK2 cells.
- Assessed renal morphology, Fe2+ levels, reactive oxygen species (ROS), and apoptosis.
- Utilized western blot to detect key proteins (TfR1, ACSL4, GPX4, Nrf2, HO-1) and performed Nrf2 knockdown experiments.
Main Results:
- GSPE treatment significantly alleviated renal impairment, oxidative stress, and ferroptosis in DKD models.
- Ferrostatin-1 (Fer-1) enhanced GSPE's anti-ferroptotic effects.
- Downregulation of Nrf2 expression diminished the anti-ferroptotic efficacy of GSPE in HK2 cells.
Conclusions:
- GSPE effectively reduces ferroptosis in DKD by modulating the Nrf2/HO-1 pathway.
- These findings highlight ferroptosis as a significant factor in DKD pathogenesis.
- GSPE demonstrates potential as a therapeutic strategy for managing DKD.
