Intravitreal Triamcinolone Acetonide Inhibits Breakdown of the Blood-Retinal Barrier Through Differential Regulation of VEGF-A and Its Receptors in Early Diabetic Rat Retinas
OBJECTIVE To elucidate the mechanism of the unique beneficial effect of intravitreal steroid therapy on diabetic macular edema, we investigated the effect of locally administered triamcinolone acetonide (TA) on the expression of vascular endothelial growth factor (VEGF)-A and its receptors in retinas of rats with streptozotocin (STZ)-induced diabetes. We then correlated the expression of these proteins with breakdown of the blood-retinal barrier (BRB).
RESEARCH DESIGN AND METHODS Thirty-two eyes of 16 diabetic and nondiabetic rats were divided into four groups. TA was injected into the vitreous of the right eye, and saline was injected into the left eye (control) 3.5 weeks after induction of diabetes. Retinas were harvested 48 h following treatment. mRNA and protein expression of VEGF-A, VEGF-A receptor 1 (fms-like tyrosine kinase [FLT]-1), and VEGF-A receptor 2 (fetal liver kinase [FLK]-1) were determined by real-time RT-PCR and immunohistochemistry. BRB permeability was quantitated by measuring extravasated endogenous albumin and retinal thickness.
RESULTS Diabetes-induced retinal thickness and albumin extravasation were significantly reduced in TA-treated diabetic retinas to a level similar to that in sham-treated nondiabetic eyes. A close correlation between albumin leakage and increased expression of both Vegf-a and Flk-1 was noted in the diabetic retinas. TA downregulated the expression of Vegf-a and Flk-1 but upregulated the expression of Flt-1. TA did not alter the expression of these genes in nondiabetic retinas.
CONCLUSIONS Intravitreal injection of TA stabilizes the BRB in association with regulation of Vegf-a, Flk-1, and Flt-1 expression in retinas in the early stages of diabetes.
M.C.G. is included as an inventor on patents relating to the formulation of triamcinolone for ocular use and its use for the treatment of retinal neovascularization, but not macular edema. M.C.G. is an advisor and receives research support from Allergan (Posurdex).
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- age-related macular degeneration
- 3-amino-9-ethylcarbazole chromogen
- blood-retinal barrier
- diabetic retinopathy
- fetal liver kinase
- fms-like tyrosine kinase
- image arbitrary unit
- Image-Pro Plus
- intravitreal injection of triamcinolone acetonide
- quantitative polymerase chain reaction
- relative expression software tool
- triamcinolone acetonide
- Tris-buffered saline
- uracil-DNA glycosylase
- vascular endothelial growth factor.
- Received July 16, 2007.
- Accepted December 19, 2007.
- © 2008 by the American Diabetes Association