Abstract
Therapeutic modalities targeting vascular endothelial growth factor (VEGF) have been used to treat neovascularization and macular edema. However, anti-VEGF treatment alone may cause up-regulation of connective tissue growth factor (CTGF) in the retina, increasing the risk of fibrosis and tractional retinal detachment. Therefore, in this study, we employ a novel dual-target intervention that involves intravitreal injection of the VEGF inhibitor ranibizumab and a transfection reagent-treated non-viral vector carrying anti-CTGF short hairpin RNA (shRNA) driven by human RNA polymerase III promoter U6. The effects of the dual-target intervention on the expression of VEGF and CTGF and on microvessel ultrastructure were examined in retina of streptozocin-induced diabetic rats. CTGF was significantly up-regulated at week 8 after diabetic induction, whereas VEGF was not up-regulated until week 10. The high expression of both genes was maintained at week 12. Transmission electron microscopy also revealed progressive exacerbation of microvessel ultrastructure during the same period. In addition, ranibizumab significantly lowered VEGF but elevated CTGF mRNA, whereas CTGF shRNA significantly reduced the mRNA levels of both CTGF and VEGF in diabetic retinas. Importantly, dual-target intervention normalized the transcript levels of both target genes and ameliorated retinal microvessel ultrastructural damage better than either single-target intervention. These results suggest the advantages of dual-target over single-target interventions in diabetic retina and reveal a novel therapeutic modality for diabetic retinopathy.
Highlights
Diabetic retinopathy (DR) is one of the most common complications associated with diabetes and is the leading cause of blindness in the working-age population
non-proliferative diabetic retinopathy (NPDR) is characterized by microvessel endothelial cell apoptosis, pericyte loss, acellular capillary formation, thickening of capillary basement membrane, and breakdown of the blood retina barrier, whereas proliferative diabetic retinopathy (PDR) is characterized by macular edema, neovascularization, retinal hemorrhage and fibrosis, and even retinal detachment [1]
The blood glucose levels in diabetic rats were all significantly higher than their normal counterparts (p < 0.001, Figure 1). These results suggest that intravenous injection of STZ induced the metabolic disorders characterized by high blood glucose, mimicking the symptoms of type I diabetes
Summary
Diabetic retinopathy (DR) is one of the most common complications associated with diabetes and is the leading cause of blindness in the working-age population. DR is divided into the early phase of non-proliferative diabetic retinopathy (NPDR) and the advanced phase of proliferative diabetic retinopathy (PDR). DR has been considered a multifactorial disease. Several pathogenic factors, including pro-inflammatory molecules [2,3], reactive oxygen species [4], diacylglycerol-protein kinase C activation [5], poly-adenosine diphosphate ribose polymerase activation [6], and the polyol pathway [7], are involved in the early phase of the disease. A variety of cytokines and growth factors promote the progression from NPDR to PDR and exacerbate the ongoing
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