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

BACKGROUND AND PURPOSE:The kinin B₁ 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 B₁ receptors in retina of streptozotocin diabetic rats. EXPERIMENTAL APPROACH:The distribution of B₁ receptors on retinal cell types was investigated by immunocytochemistry. Effects of B₁ receptor agonist, R-838, and antagonist, R-954, on retinal leukocyte adhesion, gene expression of kinin and VEGF systems, B₁ receptor immunoreactivity, microgliosis and capillary leakage were measured. Effect of B₁ receptor siRNA on gene expression was also assessed. KEY RESULTS:mRNA levels of the kinin and VEGF systems were significantly enhanced at 2 weeks in streptozotocin (STZ)-retina compared to control-retina and were further increased at 6 weeks. B₁ receptor mRNA levels remained increased at 6 months. B₁ receptor immunolabelling was detected in vascular layers of the retina, on glial and ganglion cells. Intravitreal R-838 amplified B₁ and B₂ receptor gene expression, B₁ receptor levels (immunodetection), leukostasis and vascular permeability at 2 weeks in STZ-retina. Topical application (eye drops) of R-954 reversed these increases in B₁ receptors, leukostasis and vascular permeability. Intravitreal B₁ 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 B₁ receptors on endothelial and glial cells in acute and advanced phases of DR. Topical application of the B₁ receptor antagonist R-954 seems a feasible therapeutic approach for the treatment of DR.

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