Paeoniflorin alleviated STZ-induced diabetic retinopathy via regulation of the PDI/ADAM17/MerTK pathway
Xiuting Qi1, Haiyue Guo1, Xinyue Xia2
1Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211100, China.
Background:
Diabetic retinopathy (DR) is a severe microvascular complication of diabetes and a leading cause of vision impairment in diabetic patients. The accumulation of apoptotic cells and inflammation are key pathological mechanisms in DR. The Mer tyrosine kinase (MerTK) receptor plays a critical role in maintaining retinal homeostasis. Proteolytic cleavage of MerTK by disintegrin and metalloproteinase-17 (ADAM17) disrupts MerTK-dependent clearance of apoptotic cells and diminishes its anti-inflammatory effects. Therefore, reducing the cleavage activity ADAM17's and promoting MerTK-dependent anti-inflammatory effects may represent potent strategy to alleviate DR.
Methods:
The DR mouse model was established using streptozotocin (STZ), and a high-glucose (HG)-induced in vitro model was developed using human retinal pigment epithelial (ARPE-19) cells. Relevant signaling molecules were analyzed through western blotting and immunohistochemistry.
Results:
Hyperglycemia promoted the accumulation of apoptotic cells and disrupted retinal microvascular growth. In both vivo and vitro model, MerTK expression was significantly reduced, while ADAM17 phosphorylation levels were markedly increased. In STZ-treated mice, protein disulfide isomerase (PDI) secretion initially rose but subsequently declined, whereas PDI secretion decreased under HG conditions. We then utilized paeoniflorin to increase the expression of this endogenous inhibitor of ADAM17. Results showed that paeoniflorin upregulated PDI production, suppressed ADAM17 expression, and enhanced MerTK phosphorylation in the eye tissues of STZ-induced mice. Additionally, paeoniflorin elevated the expression of suppressor of cytokine signaling 3 (SOCS3) and decreased the level of matrix metalloproteinase 9 (MMP9) both in vivo and in vitro.
Conclusion:
Paeoniflorin may alleviate diabetic retinopathy by suppressing inflammation through modulation of the PDI/ADAM17/MerTK signaling pathway.
Insights
Paeoniflorin alleviates diabetic retinopathy by reducing inflammation. It modulates the PDI/ADAM17/MerTK pathway, enhancing MerTK signaling and suppressing inflammatory markers in diabetic eye disease.
Area of Science:
- Ophthalmology
- Endocrinology
- Pharmacology
Background:
- Diabetic retinopathy (DR) is a leading cause of vision loss, characterized by apoptotic cell accumulation and inflammation.
- Mer tyrosine kinase (MerTK) is crucial for retinal homeostasis, but its function is impaired by ADAM17-mediated cleavage in DR.
- Targeting ADAM17 activity and promoting MerTK signaling offers a potential therapeutic strategy for DR.
Purpose of the Study:
- To investigate the therapeutic potential of paeoniflorin in a diabetic retinopathy (DR) mouse model and high-glucose-induced ARPE-19 cells.
- To elucidate the underlying molecular mechanisms involving the PDI/ADAM17/MerTK signaling pathway.
Main Methods:
- Established DR models using streptozotocin (STZ) in mice and high-glucose (HG) in ARPE-19 cells.
- Analyzed key signaling molecules via western blotting and immunohistochemistry.
- Investigated the effects of paeoniflorin on PDI, ADAM17, MerTK, SOCS3, and MMP9 expression and phosphorylation.
Main Results:
- Hyperglycemia induced apoptotic cell accumulation and microvascular damage, reducing MerTK and increasing ADAM17 phosphorylation.
- Paeoniflorin upregulated protein disulfide isomerase (PDI), suppressed ADAM17, and enhanced MerTK phosphorylation in DR models.
- Paeoniflorin treatment increased SOCS3 and decreased MMP9 levels, indicating reduced inflammation.
Conclusions:
- Paeoniflorin demonstrates therapeutic potential for diabetic retinopathy.
- The drug alleviates DR by suppressing inflammation via the PDI/ADAM17/MerTK signaling pathway.
- Paeoniflorin represents a promising agent for managing DR by restoring MerTK function and reducing inflammatory mediators.
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