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

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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
dc.contributor.author Dagher, Zeina
dc.contributor.author Sebastiani, Paola
dc.contributor.author Park, Yong Seek
dc.contributor.author Lorenzi, Mara
dc.date.accessioned 2011-03-04T03:50:32Z
dc.date.issued 2009
dc.identifier.citation Gerhardinger, Chiara, Zeina Dagher, Paola Sebastiani, Yong Seek Park, and Mara Lorenzi. 2009. The transforming growth factor-β pathway is a common target of drugs that prevent experimental diabetic retinopathy. Diabetes 58(7): 1659-1667. en_US
dc.identifier.issn 0012-1797 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:4737043
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.language.iso en_US en_US
dc.publisher American Diabetes Association en_US
dc.relation.isversionof doi:10.2337/db08-1008 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699853/pdf/ en_US
dash.license LAA
dc.subject complications en_US
dc.subject Aldose Reductase en_US
dc.subject Microvascular Complications en_US
dc.subject Endothelial Cells en_US
dc.subject Oxidative Stress en_US
dc.subject Gene Expression en_US
dc.subject Mesangial Cells en_US
dc.subject Polyol Pathway en_US
dc.subject Activation en_US
dc.subject Protein en_US
dc.subject Hyperglycemia 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 Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal Diabetes en_US
dash.depositing.author Lorenzi, Mara
dc.date.available 2011-03-04T03:50:32Z
dash.affiliation.other HMS^Ophthalmology en_US
dash.affiliation.other HMS^Ophthalmology en_US
dash.affiliation.other HMS^Ophthalmology en_US

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