Activation of endoplasmic reticulum stress by hyperglycemia is essential for Müller cell-derived inflammatory cytokine production in diabetes.
Inflammation plays an important role in diabetes-induced retinal vascular leakage. The purpose of this study is to examine the role of endoplasmic reticulum (ER) stress and the signaling pathway of ER stress-induced activating transcription factor 4 (ATF4) in the regulation of Müller cell-derived inflammatory mediators in diabetic retinopathy. In diabetic animals, elevated ER stress markers, ATF4, and vascular endothelial growth factor (VEGF) expression were partially localized to Müller cells in the retina. In cultured Müller cells, high glucose induced a time-dependent increase of ER stress, ATF4 expression, and inflammatory factor production. Inducing ER stress or overexpressing ATF4 resulted in elevated intracellular adhesion molecule 1 and VEGF proteins in Müller cells. In contrast, alleviation of ER stress or blockade of ATF4 activity attenuated inflammatory gene expression induced by high glucose or hypoxia. Furthermore, we found that ATF4 regulated the c-Jun NH2-terminal kinase pathway resulting in VEGF upregulation. ATF4 was also required for ER stress-induced and hypoxia-inducible factor-1α activation. Finally, we showed that administration of chemical chaperone 4-phenylbutyrate or genetic inhibition of ATF4 successfully attenuated retinal VEGF expression and reduced vascular leakage in mice with STZ-induced diabetes. Taken together, our data indicate that ER stress and ATF4 play a critical role in retinal inflammatory signaling and Müller cell-derived inflammatory cytokine production in diabetes.
Department of Medicine, Endocrinology, and Diabetes, Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Yimin
Y
Zhong
Jingming
J
Li
Yanming
Y
Chen
Joshua J
JJ
Wang
Rajiv
R
Ratan
Sarah X
SX
Zhang
D051701:Activating Transcription Factor 4 / Q000502:physiology; D021581:Active Transport, Cell Nucleus; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology*; D003930:Diabetic Retinopathy / Q000276:immunology*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006943:Hyperglycemia / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D012160:Retina / Q000276:immunology*; D013311:Streptozocin; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
C081452:Atf4 protein, mouse; D016207:Cytokines; D018836:Inflammation Mediators; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D051701:Activating Transcription Factor 4; D013311:Streptozocin; D048031:JNK Mitogen-Activated Protein Kinases