Nuclear Factor of Activated T Cells Is Activated in the Endothelium of Retinal Microvessels in Diabetic Mice

Journal of Diabetes Research - Tập 2015 - Trang 1-14 - 2015
Anna V. Zetterqvist1, Fabiana Blanco2,1, Jenny Öhman1, Olga Kotova1, Lisa M. Berglund1, Sergio de Frutos3, Raed Salim Al-Naemi1, Maria Wigren1, Paul G. McGuire3, Laura V. González Bosc3, Maria F. Gomez1
1Department of Clinical Sciences in Malmö, Lund University, 20502 Malmö, Sweden
2Departamento de Biofísica, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay
3Department of Cell Biology and Physiology, University of New Mexico, Health Sciences Center, Albuquerque, NM 87131, USA

Tóm tắt

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 vivoinhibition of NFAT with A-285222 decreased the expression ofOPNandICAM-1mRNA 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.

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Tài liệu tham khảo

10.1038/414813a

10.1161/01.ATV.0000209513.00765.13

10.1161/ATVBAHA.109.199299

10.1113/jphysiol.2003.047977

10.1002/jnr.21956

10.1155/2007/95103

10.1152/ajpcell.00590.2005

10.1093/hmg/ddp511

10.1371/journal.pone.0065020

10.1182/blood-2004-01-0273

2008, Arteriosclerosis, Thrombosis, and Vascular Biology, 29, 225

1995, The American Journal of Pathology, 147, 642

10.1136/bjo.59.11.649

10.1074/jbc.274.33.23463

10.1016/j.cmet.2013.09.003

10.1084/jem.193.5.607

10.1167/iovs.13-12183

10.1242/jcs.115550

10.1038/nm.1877

10.1161/01.res.0000109415.17511.18

10.1371/journal.pone.0012699

2004, Journal of Vascular Research, 41, 314, 10.1159/000079205

10.1167/iovs.04-1340

10.1074/jbc.m304765200

10.1016/j.yjmcc.2009.06.010

10.1016/j.ceca.2006.10.006

10.1007/s12031-013-0198-y

10.2337/dc08-s241

10.2337/db05-1263

10.2174/138161207781662920

10.1159/000098497

10.1016/j.ajo.2006.07.032

10.1136/bjo.2006.109876

10.1111/j.1464-5491.2008.02466.x

10.1016/j.clinbiochem.2006.03.013

10.1111/j.1365-3083.2007.02054.x

10.1136/bjo.2003.038133

10.2337/db06-0427

10.1016/s0021-5155(01)00452-x

10.1097/00006982-200110000-00009

2002, The FASEB Journal, 16, 438, 10.1096/fj.01-0707fje

10.1155/2013/106594

10.1161/atvbaha.109.193862

10.1016/j.molimm.2008.07.037

10.1084/jem.20100414

10.1161/HYPERTENSIONAHA.109.137158

10.1159/000102936

10.1152/ajpcell.00322.2008

10.1167/iovs.10-5768

10.2337/db06-1694

2001, The Journal of Biological Chemistry, 276, 48118, 10.1074/jbc.M107919200

2004, Transplant International, 17, 145, 10.1007/s00147-003-0676-1

10.2337/dc13-2002

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Journal of Diabetes Research

Tập 2015

1-14

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