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).


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.
Zhang
Xinyuan
X
Save Sight Institute, Department of Clinical Ophthalmology, University of Sydney, Sydney, Australia. xzhang@eye.usyd.edu.au
Bao
Shisan
S
Lai
Donna
D
Rapkins
Robert W
RW
Gillies
Mark C
MC
D000818:Animals; D001813:Blood-Retinal Barrier / Q000187:drug effects / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000235:genetics; D018450:Disease Progression; D005938:Glucocorticoids / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014222:Triamcinolone Acetonide / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects / Q000235:genetics*
D005938:Glucocorticoids; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D040301:Vascular Endothelial Growth Factor Receptor-2; D014222:Triamcinolone Acetonide