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

• Published in: Diabetes (New York, N.Y.) Vol. 58; no. 7; pp. 1659 - 1667
• Main Authors: GERHARDINGER, Chiara, DAGHER, Zeina, SEBASTIANI, Paola, YONG SEEK PARK, LORENZI, Mara
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.07.2009
• Subjects: Animal models in research; Animal research models; Animals; Aspirin - pharmacology; Biological and medical sciences; Control; Diabetes Mellitus, Experimental - physiopathology; Diabetes. Impaired glucose tolerance; Diabetic retinopathy; Diabetic Retinopathy - genetics; Diabetic Retinopathy - physiopathology; Diabetic Retinopathy - prevention & control; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene Expression Profiling; Gene Expression Regulation - drug effects; Genetic aspects; Health aspects; Imidazolidines - pharmacology; Immunohistochemistry; Inflammation - genetics; Inflammation - physiopathology; Medical sciences; Methods; Oligonucleotide Array Sequence Analysis; Ophthalmology; Original; Oxidative Stress - genetics; Prevention; Rats; Receptors, Transforming Growth Factor beta - physiology; Retina - physiopathology; Retinal Vessels - physiopathology; Retinopathies; Reverse Transcriptase Polymerase Chain Reaction; RNA - genetics; RNA - isolation & purification; Transforming Growth Factor beta - drug effects; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - physiology; Transforming growth factors; United States; Endocrinopathy; Eye disease; Retinopathy; Transforming growth factor β; Diabetes mellitus
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db08-1008

The Transforming Growth Factor-β Pathway Is a Common Target of Drugs That Prevent Experimental Diabetic Retinopathy Chiara Gerhardinger 1 , Zeina Dagher 1 , Paola Sebastiani 2 , Yong Seek Park 1 and Mara Lorenzi 1 1 Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; 2 Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts. Corresponding author: Chiara Gerhardinger, chiara.gerhardinger{at}schepens.harvard.edu . 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. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received July 24, 2008. Accepted April 2, 2009. 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. © 2009 by the American Diabetes Association.