The blood-retinal barrier (BRB) is a biological unit comprised of specialized capillary endothelial cells firmly connected by intercellular tight junctions and endotheliumsurrounding glial cells. The BRB is essential for maintaining the retinal microenvironment and low permeability and is compromised in an early phase during the progression of diabetic retinopathy. Here, we demonstrate that retinoic acid receptor (RAR)␣ stimulants preferentially act on glial cells rather than endothelial cells,

more »

... resulting in the enhanced expression of glial cell line-derived neurotrophic factor (GDNF) through recruitment of the RAR␣-driven trans-acting coactivator to the 5-flanking region of the gene promoter. Conversely, RAR␣ decreases expression of vascular endothelial growth factor (VEGF)/vascular permeability factor. These gene expression alterations causally limit vascular permeability by modulating the tight junction function of capillary endothelium in a paracrine manner in vitro. The phenotypic transformation of glial cells mediated by RAR␣ is sufficient for significant reductions of vascular leakage in the diabetic retina, suggesting that RAR␣ antagonizes the loss of tight junction integrity induced by diabetes. These findings reveal that glial cell-derived cytokines such as GDNF and VEGF regulate BRB function, implying that the glial cell can be a possible therapeutic target in diabetic retinopathy. Diabetes 56:1333-1340, 2007 RESEARCH DESIGN AND METHODS Cell culture and treatment. The human glioblastoma cell line U373MG and endothelial cells cultured using the bovine brain microvascular endothelial From the