Expression, distribution and function of kinin B1 receptor in the rat diabetic retina

Background and Purpose The kinin B-1 receptor contributes to vascular inflammation and blood-retinal barrier breakdown in diabetic retinopathy (DR). We investigated the changes in expression, cellular localization and vascular inflammatory effect of B-1 receptors in retina of streptozotocin diabetic rats. Experimental Approach The distribution of B-1 receptors on retinal cell types was investigated by immunocytochemistry. Effects of B-1 receptor agonist, R-838, and antagonist, R-954, on retinal leukocyte adhesion, gene expression of kinin and VEGF systems, B-1 receptor immunoreactivity, microgliosis and capillary leakage were measured. Effect of B-1 receptor siRNA on gene expression was also assessed. Key Results mRNA levels of the kinin and VEGF systems were significantly enhanced at 2weeks in streptozotocin (STZ)-retina compared to control-retina and were further increased at 6weeks. B-1 receptor mRNA levels remained increased at 6months. B-1 receptor immunolabelling was detected in vascular layers of the retina, on glial and ganglion cells. Intravitreal R-838 amplified B-1 and B-2 receptor gene expression, B-1 receptor levels (immunodetection), leukostasis and vascular permeability at 2weeks in STZ-retina. Topical application (eye drops) of R-954 reversed these increases in B-1 receptors, leukostasis and vascular permeability. Intravitreal B-1 receptor siRNA inhibited gene expression of kinin and VEGF systems in STZ-retina. Microgliosis was unaffected by R-838 or R-954 in STZ-retina. Conclusion and Implications Our results support the detrimental role of B-1 receptors on endothelial and glial cells in acute and advanced phases of DR. Topical application of the B-1 receptor antagonist R-954 seems a feasible therapeutic approach for the treatment of DR.