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In vivo inhibition of Nuclear Factor of Activated T‐cells (NFAT) results in enhanced levels of anti‐inflammatory IL‐10 in the retina of diabetic mice
Author(s) -
Zetterqvist Anna V,
NilssonÖhman Jenny,
Kotova Olga,
NilssonBerglund Lisa M,
Frutos Garcia Sergio,
McGuire Paul,
GonzalezBosc Laura V,
Gomez Maria F
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.777.17
Subject(s) - nfat , calcineurin , endocrinology , medicine , apyrase , chemistry , biology , microbiology and biotechnology , pharmacology , transplantation , receptor
Hyperglycemia is an important risk factor for the development of diabetic retinopathy. Recently we showed that high glucose activates NFAT in cerebral artery smooth muscle through local release of extracellular nucleotides, acting on P2Y receptors, leading to increased [Ca 2+ ] i and calcineurin activation. NFAT activation promotes cell proliferation and the expression of inflammatory markers, such as IL‐6, COX‐2 and osteopontin, which are elevated in diabetic retinopathy. Here we investigate whether: 1) NFAT is activated by hyperglycemia in the wall of retinal microvessels (RM) and 2) inhibition of NFAT signaling may have a protective effect on the retina of diabetic mice. Using confocal immunofluorescence microscopy we show that NFATc3 is expressed in the endothelium of RM and readily activated by high glucose ex vivo and in vivo (intra peritoneal glucose tolerance test). This activation is inhibited by the NFAT blocker A‐285222 and by the ecto‐nucleotidase apyrase. Chronic hyperglycemia in STZ‐treated NFAT‐luc mice leads to increased NFAT transcriptional activity in isolated RM. Interestingly, two weeks after the first STZ injection, levels of the potent anti‐inflammatory cytokine IL‐10 were decreased in retina and this was prevented by treatment with A‐285222. Results suggest that NFAT inhibition may protect the retina of diabetic mice. Funding: Swedish Heart & Lung Foundations, RAC HSC‐UNM 624195