Vascular basement membrane thickening is a prominent and characteristic lesion of diabetic retinopathy. The goal of this project is to test the hypothesis that the thickened vascular basement membrane (BM) occurring in diabetes plays a role in the development and progression of serious structural and functional abnormalities of diabetic retinopathy. The hypothesis is based on recent findings that human retinal vessels manifest alterations that can be induced by the thickened BMs and, in turn, can compromise the integrity of the vessels' inner lining. In retinal capillary cells of diabetic individuals there is increased production of the BM proteins, fibronectin (FN), collagen IV (coil IV), and laminin (LM). Antisense oligonucleotides developed in our laboratory specifically down-regulate overexpression of the three BM components in microvascular endothelial cells grown in high glucose medium. Furthermore, inhibition of FN overexpression with the FN antisense oligonucleotide partially prevented the development of thickened vascular BM in retinal capillaries of galactose-fed rats, an animal model of diabetic retinopathy, with beneficial consequences to histological lesions. To completely prevent or reverse vascular BM thickening, and regulate functional abnormalities, the development of a more effective antisense strategy is necessary. Having identified antisense oligos that independently down-regulate FN, coil IV or LM expression in retinal vascular cells, in the proposed studies we plan to: (1) Establish whether combined antisense oligo approach prevents vascular BM thickening in rat retinas, and affects FN, coil IV, LM turnover in matrix. (2) Determine if downregulation of the specific BM genes reverses BM thickening, reduces vascular lesions, and affects cellular processes in retinas of diabetic rats. (3) Determine whether high glucose-induced or diabetes-induced altered expression of BM components plays a role in vascular permeability. FN, coil IV, and LM protein level will be monitored by Western blot analysis and immunohistochemistry; RNA level will be analyzed by RT-PCR. Retinal capillary BM width will be measured by morphometric analysis of electron micrographs. Vascular lesions will be assessed from retinal trypsin digests and image analysis. Findings from this project will establish or exclude a pathogenetic link between a discrete biosynthetic abnormality and the development of structural and functional lesions of diabetic retinopathy.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-VISC (01))
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Shen, Grace L
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Boston University
Schools of Medicine
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Roy, Sumon; Kim, Dongjoon; Hernández, Cristina et al. (2015) Beneficial effects of fenofibric acid on overexpression of extracellular matrix components, COX-2, and impairment of endothelial permeability associated with diabetic retinopathy. Exp Eye Res 140:124-129
Trudeau, Kyle; Roy, Sumon; Guo, Wen et al. (2011) Fenofibric acid reduces fibronectin and collagen type IV overexpression in human retinal pigment epithelial cells grown in conditions mimicking the diabetic milieu: functional implications in retinal permeability. Invest Ophthalmol Vis Sci 52:6348-54
Roy, Sumon; Nasser, Sigrid; Yee, Melissa et al. (2011) A long-term siRNA strategy regulates fibronectin overexpression and improves vascular lesions in retinas of diabetic rats. Mol Vis 17:3166-74
Trudeau, Kyle; Molina, Anthony J A; Roy, Sayon (2011) High glucose induces mitochondrial morphology and metabolic changes in retinal pericytes. Invest Ophthalmol Vis Sci 52:8657-64
Roy, Sayon; Ha, John; Trudeau, Kyle et al. (2010) Vascular basement membrane thickening in diabetic retinopathy. Curr Eye Res 35:1045-56
Chronopoulos, Argyrios; Tang, Amanda; Beglova, Ekaterina et al. (2010) High glucose increases lysyl oxidase expression and activity in retinal endothelial cells: mechanism for compromised extracellular matrix barrier function. Diabetes 59:3159-66
Alikhani, Mani; Roy, Sayon; Graves, Dana T (2010) FOXO1 plays an essential role in apoptosis of retinal pericytes. Mol Vis 16:408-15
Roy, Sumon; Tonkiss, John; Roy, Sayon (2010) Aging increases retinal vascular lesions characteristic of early diabetic retinopathy. Biogerontology 11:447-55
Li, An-Fei; Roy, Sayon (2009) High glucose-induced downregulation of connexin 43 expression promotes apoptosis in microvascular endothelial cells. Invest Ophthalmol Vis Sci 50:1400-7
Behl, Yugal; Krothapalli, Padmaja; Desta, Tesfahun et al. (2009) FOXO1 plays an important role in enhanced microvascular cell apoptosis and microvascular cell loss in type 1 and type 2 diabetic rats. Diabetes 58:917-25

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