2. Academic Validation
  3. Paeoniflorin alleviated STZ-induced diabetic retinopathy via regulation of the PDI/ADAM17/MerTK pathway

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

  • Int Immunopharmacol. 2025 May 16:155:114571. doi: 10.1016/j.intimp.2025.114571.
Xiuting Qi 1,  Haiyue Guo 1,  Xinyue Xia 2,  Yanmei Liu 3,  Shenghui Qiu 1,  Tongtong Lin 4,  Wenqi He 1,  Lai Jin 1,  Jing Cheng 5,  Lanxiang Hao 6,  Wentao Liu 7,  Haitao Hu 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211100, China.
  • 2 The First Clinical College, Nanjing Medical University, Nanjing 211166, China.
  • 3 The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Jiangsu 224005, China.
  • 4 State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligence Manufacture, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
  • 5 Department of Gastroenterology, Lianyungang Municipal Oriental Hospital, Lianyungang, Jiangsu, China; Department of Gastroenterology,Shanghai General Hospial of Nanjing Medical University, Shanghai, China.
  • 6 The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Jiangsu 224005, China. Electronic address: haolanfang@sina.com.
  • 7 Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211100, China. Electronic address: painresearch@njmu.edu.cn.
  • 8 The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Jiangsu 224005, China. Electronic address: huhaitao2302@163.com.
PMID: 40209310 DOI: 10.1016/j.intimp.2025.114571
Abstract

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.

Keywords

ADAM17; MMP9; MerTK; PDI; Paeoniflorin; SOCS3.

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