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Zhi Zheng, Haibing Chen, Hui Zhao, Kun Liu, Dawei Luo, Yongdong Chen, Yihui Chen, Xiaolu Yang, Qing Gu, Xun Xu; Inhibition of JAK2/STAT3-Mediated VEGF Upregulation under High Glucose Conditions by PEDF through a Mitochondrial ROS Pathway In Vitro. Invest. Ophthalmol. Vis. Sci. 2010;51(1):64-71. doi: https://doi.org/10.1167/iovs.09-3511.
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Hyperglycemia-induced mitochondrial reactive oxygen species (ROS) production plays an important role in the development of complications of diabetes such as retinopathy. However, whether pigment epithelium–derived factor (PEDF) can decrease ROS production remains uncertain. The aim of this study was to clarify whether PEDF can decrease mitochondria-derived ROS generation and subsequently downregulate vascular endothelial growth factor (VEGF) expression; the authors also investigated the involvement of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) in the process.
Bovine retinal capillary endothelial cells (BRECs) were exposed to normal glucose (NG), H2O2, or high glucose (HG) in the presence or absence of PEDF. Expression of JAK2/STAT3, VEGF, uncoupling protein (UCP)-2, and proliferator-activated receptor gamma (PPARγ) in the BRECs was examined by Western blot analysis assay; VEGF and UCP-2 mRNA were determined by real-time RT-PCR. Mitochondrial membrane potential (Δψm) and ROS production were assayed using JC-1 and CM-H2DCFDA, respectively.
HG exposure caused hyperpolarization of Δψm and increased ROS generation in BRECs; meanwhile, like H2O2, it also induced the phosphorylation of JAK2/STAT3 and increased VEGF expression; these changes were inhibited by PEDF. The authors also found that PEDF-induced ROS inhibition was a result of decreased Δψm, which was caused by the upregulation of PPARγ and UCP-2 expression.
For the first time it has been demonstrated that PEDF can decrease mitochondria-derived ROS generation and subsequently downregulate VEGF expression, possibly through inhibiting HG-induced JAK2/STAT3 activation, which may offer a promising strategy for halting the development of complications of diabetes.
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