Inhibition of JAK2/STAT3-Mediated VEGF Upregulation under High Glucose Conditions by PEDF through a Mitochondrial ROS Pathway In Vitro

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PURPOSE: 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. METHODS: Bovine retinal capillary endothelial cells (BRECs) were exposed to normal glucose (NG), H(2)O(2), 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 (PPARgamma) 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 (Deltapsim) and ROS production were assayed using JC-1 and CM-H2DCFDA, respectively. RESULTS: HG exposure caused hyperpolarization of Deltapsim and increased ROS generation in BRECs; meanwhile, like H(2)O(2), 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 Deltapsim, which was caused by the upregulation of PPARgamma and UCP-2 expression. CONCLUSIONS: 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.