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Endothelial STAT3 Activation Increases Vascular Leakage Through Downregulating Tight Junction Proteins: Implications for Diabetic Retinopathy
Author(s) -
Yun JangHyuk,
Park Sung Wook,
Kim KyungJin,
Bae JongSup,
Lee Eun Hui,
Paek Sun Ha,
Kim Seung U.,
Ye Sangkyu,
Kim JeongHun,
Cho ChungHyun
Publication year - 2017
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.25575
Subject(s) - occludin , vascular permeability , endothelial stem cell , microbiology and biotechnology , stat3 , inflammation , blood–retinal barrier , vascular endothelial growth factor a , diabetic retinopathy , vascular endothelial growth factor , retinal , cancer research , tight junction , biology , chemistry , immunology , signal transduction , endocrinology , diabetes mellitus , biochemistry , in vitro , vegf receptors
Vascular inflammation is characteristic feature of diabetic retinopathy. In diabetic retina, a variety of the pro‐inflammatory cytokines are elevated and involved in endothelial dysfunction. STAT3 transcription factor has been implicated in mediating cytokine signaling during vascular inflammation. However, whether and how STAT3 is involved in the direct regulation of the endothelial permeability is currently undefined. Our studies revealed that IL‐6‐induced STAT3 activation increases retinal endothelial permeability and vascular leakage in retinas of mice through the reduced expression of the tight junction proteins ZO‐1 and occludin. In a co‐culture model with microglia and endothelial cells under a high glucose condition, the microglia‐derived IL‐6 induced STAT3 activation in the retinal endothelial cells, leading to increasing endothelial permeability. In addition, IL‐6‐induced STAT3 activation was independent of ROS generation in the retinal endothelial cells. Moreover, we demonstrated that STAT3 activation downregulates the ZO‐1 and occludin levels and increases the endothelial permeability through the induction of VEGF production in retinal endothelial cells. These results suggest the potential importance of IL‐6/STAT3 signaling in regulating endothelial permeability and provide a therapeutic target to prevent the pathology of diabetic retinopathy. J. Cell. Physiol. 232: 1123–1134, 2017. © 2016 Wiley Periodicals, Inc.