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The Transforming Growth Factor-β Pathway Is a Common Target of Drugs That Prevent Experimental Diabetic Retinopathy

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dc.contributor.author Gerhardinger, Chiara en_US
dc.contributor.author Dagher, Zeina en_US
dc.contributor.author Sebastiani, Paola en_US
dc.contributor.author Park, Yong Seek en_US
dc.contributor.author Lorenzi, Mara en_US
dc.date.accessioned 2011-12-29T22:21:54Z
dc.date.available 2011-12-29T22:21:54Z
dc.date.issued 2009-4-28 en_US
dc.identifier.citation Gerhardinger, Chiara, Zeina Dagher, Paola Sebastiani, Yong Seek Park, Mara Lorenzi. "The Transforming Growth Factor-β Pathway Is a Common Target of Drugs That Prevent Experimental Diabetic Retinopathy" Diabetes 58(7): 1659-1667. (2009) en_US
dc.identifier.issn 1939-327X en_US
dc.identifier.uri http://hdl.handle.net/2144/2575
dc.description.abstract OBJECTIVE: Prevention of diabetic retinopathy would benefit from availability of drugs that preempt the effects of hyperglycemia on retinal vessels. We aimed to identify candidate drug targets by investigating the molecular effects of drugs that prevent retinal capillary demise in the diabetic rat. RESEARCH DESIGN AND METHODS: We examined the gene expression profile of retinal vessels isolated from rats with 6 months of streptozotocin-induced diabetes and compared it with that of control rats. We then tested whether the aldose reductase inhibitor sorbinil and aspirin, which have different mechanisms of action, prevented common molecular abnormalities induced by diabetes. The Affymetrix GeneChip Rat Genome 230 2.0 array was complemented by real-time RT-PCR, immunoblotting, and immunohistochemistry. RESULTS: The retinal vessels of diabetic rats showed differential expression of 20 genes of the transforming growth factor (TGF)-β pathway, in addition to genes involved in oxidative stress, inflammation, vascular remodeling, and apoptosis. The complete loop of TGF-β signaling, including Smad2 phosphorylation, was enhanced in the retinal vessels, but not in the neural retina. Sorbinil normalized the expression of 71% of the genes related to oxidative stress and 62% of those related to inflammation. Aspirin had minimal or no effect on these two categories. The two drugs were instead concordant in reducing the upregulation of genes of the TGF-β pathway (55% for sorbinil and 40% for aspirin) and apoptosis (74 and 42%, respectively). CONCLUSIONS: Oxidative and inflammatory stress is the distinct signature that the polyol pathway leaves on retinal vessels. TGF-β and apoptosis are, however, the ultimate targets to prevent the capillary demise in diabetic retinopathy. en_US
dc.description.sponsorship National Institutes of Health (R01EY016206, R01EY017637, R01HG003354),; the Juvenile Diabetes Research Foundation Center for Diabetic Retinopathy at the Schepens Eye Research Institute; Massachusetts Lions Eye Research Fund; George and Frances Levin Endowment en_US
dc.language.iso en en_US
dc.publisher American Diabetes Association en_US
dc.rights © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. en_US
dc.title The Transforming Growth Factor-β Pathway Is a Common Target of Drugs That Prevent Experimental Diabetic Retinopathy en_US
dc.type article en_US
dc.identifier.doi 10.2337/db08-1008 en_US
dc.identifier.pubmedid 19401417 en_US
dc.identifier.pmcid 2699853 en_US


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