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Sestrin2 ameliorates diabetic retinopathy by regulating autophagy and ferroptosis
Xiaoting Xi1, Qianbo Chen1, Jia Ma1
1Ophthalmology Department, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, China.
Abstract:
Diabetic retinopathy (DR) is a serious microvascular complication of diabetes. The aim of this study was to explore the effect of Sestrin2 on DR through the regulation of autophagy and ferroptosis levels and its mechanism. In vitro and in vivo DR models were established by high glucose (HG) and streptozotocin (STZ) induction of ARPE-19 human retinal pigment epithelial cells and C57BL/6 mice, respectively. In this study, we demonstrated that after HG treatment, the activity of ARPE-19 cells was decreased, the apoptosis rate was increased, endoplasmic reticulum (ER) stress was activated, autophagy levels were decreased, and ferroptosis levels were increased. Overexpression of Sestrin2 enhanced cell viability, reduced apoptosis and ferroptosis, and enhanced autophagy. However, the effect of overexpression of Sestrin2 was attenuated after the addition of the STAT3 phosphorylation activator Colivelin TFA (C-TFA), the mTOR pathway activator MHY1485 or the autophagy inhibitor 3-methyladenine (3-MA). In addition, the effect of Sestrin2 knockdown on cells was opposite to the effect of overexpression of Sestrin2, while the effect of Sestrin2 knockdown was attenuated after treatment with the ER stress inhibitor 4-phenylbutyric acid (4-PBA). Animal experiments also confirmed the results of cell experiments and attenuated the effects of overexpression of Sestrin2 after injection of the ferroptosis activators erastin or 3-MA. Our study revealed that Sestrin2 inhibits ferroptosis by inhibiting STAT3 phosphorylation and ER stress and promoting autophagy levels, thereby alleviating DR.
Insights
Sestrin2 protects against diabetic retinopathy (DR) by reducing cell death and promoting autophagy. It achieves this by inhibiting STAT3 phosphorylation, endoplasmic reticulum stress, and ferroptosis, offering a potential therapeutic target for DR.
Area of Science:
- Ophthalmology
- Endocrinology
- Cell Biology
Background:
- Diabetic retinopathy (DR) is a severe microvascular complication of diabetes.
- Understanding the molecular mechanisms underlying DR is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of Sestrin2 in diabetic retinopathy.
- To explore the mechanisms involving autophagy and ferroptosis in Sestrin2's effect on DR.
Main Methods:
- Established in vitro (ARPE-19 cells) and in vivo (C57BL/6 mice) models of DR using high glucose and streptozotocin.
- Assessed cell viability, apoptosis, endoplasmic reticulum stress, autophagy, and ferroptosis.
- Utilized Sestrin2 overexpression and knockdown, along with specific pathway activators and inhibitors.
Main Results:
- High glucose treatment decreased cell viability and increased apoptosis, ER stress, and ferroptosis, while reducing autophagy.
- Sestrin2 overexpression reversed these effects, enhancing viability and autophagy while reducing apoptosis and ferroptosis.
- Inhibitors and activators of STAT3, mTOR, autophagy, and ER stress modulated Sestrin2's protective effects.
Conclusions:
- Sestrin2 alleviates diabetic retinopathy by inhibiting ferroptosis, STAT3 phosphorylation, and ER stress.
- Sestrin2 promotes autophagy, contributing to its protective role in DR.
- Sestrin2 represents a promising therapeutic target for managing diabetic retinopathy.
