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Int. J. Mol. Sci. 2014, 15(1), 1606-1624; doi:10.3390/ijms15011606

Intravitreal Injection of Ranibizumab and CTGF shRNA Improves Retinal Gene Expression and Microvessel Ultrastructure in a Rodent Model of Diabetes

Tianjin Medical University Eye Hospital/Eye Institute, Fukang Rd. 251#, Nankai Dist., Tianjin 300384, China
These authors contributed equally to this work.
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Received: 1 November 2013 / Revised: 10 January 2014 / Accepted: 13 January 2014 / Published: 22 January 2014
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
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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.
Keywords: vascular endothelial growth factor; connective tissue growth factor; diabetic retinopathy; ranibizumab; shRNA vascular endothelial growth factor; connective tissue growth factor; diabetic retinopathy; ranibizumab; shRNA
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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Hu, B.; Zhang, Y.; Zeng, Q.; Han, Q.; Zhang, L.; Liu, M.; Li, X. Intravitreal Injection of Ranibizumab and CTGF shRNA Improves Retinal Gene Expression and Microvessel Ultrastructure in a Rodent Model of Diabetes. Int. J. Mol. Sci. 2014, 15, 1606-1624.

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