Nuclear Factor of Activated T Cells Is Activated in the Endothelium of Retinal Microvessels in Diabetic Mice
The pathogenesis of diabetic retinopathy (DR) remains unclear but hyperglycemia is an established risk factor. Endothelial dysfunction and changes in Ca2+ signaling have been shown to precede the onset of DR. We recently demonstrated that high extracellular glucose activates the Ca2+/calcineurin-dep...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2015-01-01
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| Series: | Journal of Diabetes Research |
| Online Access: | http://dx.doi.org/10.1155/2015/428473 |
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| author | Anna V. Zetterqvist Fabiana Blanco Jenny Öhman Olga Kotova Lisa M. Berglund Sergio de Frutos Garcia Raed Al-Naemi Maria Wigren Paul G. McGuire Laura V. Gonzalez Bosc Maria F. Gomez |
| author_facet | Anna V. Zetterqvist Fabiana Blanco Jenny Öhman Olga Kotova Lisa M. Berglund Sergio de Frutos Garcia Raed Al-Naemi Maria Wigren Paul G. McGuire Laura V. Gonzalez Bosc Maria F. Gomez |
| author_sort | Anna V. Zetterqvist |
| collection | DOAJ |
| description | The pathogenesis of diabetic retinopathy (DR) remains unclear but hyperglycemia is an established risk factor. Endothelial dysfunction and changes in Ca2+ signaling have been shown to precede the onset of DR. We recently demonstrated that high extracellular glucose activates the Ca2+/calcineurin-dependent transcription factor NFAT in cerebral arteries and aorta, promoting the expression of inflammatory markers. Here we show, using confocal immunofluorescence, that NFAT is expressed in the endothelium of retinal microvessels and is readily activated by high glucose. This was inhibited by the NFAT blocker A-285222 as well as by the ectonucleotidase apyrase, suggesting a mechanism involving the release of extracellular nucleotides. Acute hyperglycemia induced by an IP-GTT (intraperitoneal glucose tolerance test) resulted in increased NFATc3 nuclear accumulation and NFAT-dependent transcriptional activity in retinal vessels of NFAT-luciferase reporter mice. In both Akita (Ins2+/−) and streptozotocin- (STZ-) induced diabetic mice, NFAT transcriptional activity was elevated in retinal vessels. In vivo inhibition of NFAT with A-285222 decreased the expression of OPN and ICAM-1 mRNA in retinal vessels, prevented a diabetes driven downregulation of anti-inflammatory IL-10 in retina, and abrogated the increased vascular permeability observed in diabetic mice. Results identify NFAT signaling as a putative target for treatment of microvascular complications in diabetes. |
| format | Article |
| id | doaj-art-fab0deb1bf574e6bbe9a6252d6270bd2 |
| institution | OA Journals |
| issn | 2314-6745 2314-6753 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Research |
| spelling | doaj-art-fab0deb1bf574e6bbe9a6252d6270bd22025-08-20T02:22:37ZengWileyJournal of Diabetes Research2314-67452314-67532015-01-01201510.1155/2015/428473428473Nuclear Factor of Activated T Cells Is Activated in the Endothelium of Retinal Microvessels in Diabetic MiceAnna V. Zetterqvist0Fabiana Blanco1Jenny Öhman2Olga Kotova3Lisa M. Berglund4Sergio de Frutos Garcia5Raed Al-Naemi6Maria Wigren7Paul G. McGuire8Laura V. Gonzalez Bosc9Maria F. Gomez10Department of Clinical Sciences in Malmö, Lund University, 20502 Malmö, SwedenDepartment of Clinical Sciences in Malmö, Lund University, 20502 Malmö, SwedenDepartment of Clinical Sciences in Malmö, Lund University, 20502 Malmö, SwedenDepartment of Clinical Sciences in Malmö, Lund University, 20502 Malmö, SwedenDepartment of Clinical Sciences in Malmö, Lund University, 20502 Malmö, SwedenDepartment of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USADepartment of Clinical Sciences in Malmö, Lund University, 20502 Malmö, SwedenDepartment of Clinical Sciences in Malmö, Lund University, 20502 Malmö, SwedenDepartment of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USADepartment of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USADepartment of Clinical Sciences in Malmö, Lund University, 20502 Malmö, SwedenThe pathogenesis of diabetic retinopathy (DR) remains unclear but hyperglycemia is an established risk factor. Endothelial dysfunction and changes in Ca2+ signaling have been shown to precede the onset of DR. We recently demonstrated that high extracellular glucose activates the Ca2+/calcineurin-dependent transcription factor NFAT in cerebral arteries and aorta, promoting the expression of inflammatory markers. Here we show, using confocal immunofluorescence, that NFAT is expressed in the endothelium of retinal microvessels and is readily activated by high glucose. This was inhibited by the NFAT blocker A-285222 as well as by the ectonucleotidase apyrase, suggesting a mechanism involving the release of extracellular nucleotides. Acute hyperglycemia induced by an IP-GTT (intraperitoneal glucose tolerance test) resulted in increased NFATc3 nuclear accumulation and NFAT-dependent transcriptional activity in retinal vessels of NFAT-luciferase reporter mice. In both Akita (Ins2+/−) and streptozotocin- (STZ-) induced diabetic mice, NFAT transcriptional activity was elevated in retinal vessels. In vivo inhibition of NFAT with A-285222 decreased the expression of OPN and ICAM-1 mRNA in retinal vessels, prevented a diabetes driven downregulation of anti-inflammatory IL-10 in retina, and abrogated the increased vascular permeability observed in diabetic mice. Results identify NFAT signaling as a putative target for treatment of microvascular complications in diabetes.http://dx.doi.org/10.1155/2015/428473 |
| spellingShingle | Anna V. Zetterqvist Fabiana Blanco Jenny Öhman Olga Kotova Lisa M. Berglund Sergio de Frutos Garcia Raed Al-Naemi Maria Wigren Paul G. McGuire Laura V. Gonzalez Bosc Maria F. Gomez Nuclear Factor of Activated T Cells Is Activated in the Endothelium of Retinal Microvessels in Diabetic Mice Journal of Diabetes Research |
| title | Nuclear Factor of Activated T Cells Is Activated in the Endothelium of Retinal Microvessels in Diabetic Mice |
| title_full | Nuclear Factor of Activated T Cells Is Activated in the Endothelium of Retinal Microvessels in Diabetic Mice |
| title_fullStr | Nuclear Factor of Activated T Cells Is Activated in the Endothelium of Retinal Microvessels in Diabetic Mice |
| title_full_unstemmed | Nuclear Factor of Activated T Cells Is Activated in the Endothelium of Retinal Microvessels in Diabetic Mice |
| title_short | Nuclear Factor of Activated T Cells Is Activated in the Endothelium of Retinal Microvessels in Diabetic Mice |
| title_sort | nuclear factor of activated t cells is activated in the endothelium of retinal microvessels in diabetic mice |
| url | http://dx.doi.org/10.1155/2015/428473 |
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