Paeoniflorin alleviated STZ-induced diabetic retinopathy via regulation of the PDI/ADAM17/MerTK pathway

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. 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. 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. Paeoniflorin may alleviate diabetic retinopathy by suppressing inflammation through modulation of the PDI/ADAM17/MerTK signaling pathway.