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

ABSTRACT: 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.

SUBMITTER: Hachana S

PROVIDER: S-EPMC5825301 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Expression, distribution and function of kinin B<sub>1</sub> receptor in the rat diabetic retina.

Hachana Soumaya S Bhat Menakshi M Sénécal Jacques J Huppé-Gourgues Frédéric F Couture Réjean R Vaucher Elvire E

British journal of pharmacology 20180213 6

<h4>Background and purpose</h4>The kinin B<sub>1</sub> 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<sub>1</sub> receptors in retina of streptozotocin diabetic rats.<h4>Experimental approach</h4>The distribution of B<sub>1</sub> receptors on retinal cell types was investigated by immunocytochemistry. Effects of B<sub>1</sub> rece ...[more]

PMID: 29285756

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Project description:Diabetic retinopathy, a retinal vascular disease, is inhibited in animals treated with aminoguanidine, an inhibitor of inducible nitric-oxide synthase. This treatment also reduces retinal protein nitration, which is greater in diabetic rat retina than nondiabetic retina. As an approach to understanding the molecular mechanisms of diabetic retinopathy, we sought the identity of nitrotyrosine-containing proteins in retina from streptozotocin-induced diabetic rats and in a rat retinal Müller cell line grown in high glucose (25 mM). Anti-nitrotyrosine immunoprecipitation products from rat retina and Müller cells were analyzed by LC-MS/MS. Ten nitrated proteins in diabetic rat retina and three nitrated proteins in Müller cells grown in high glucose were identified; three additional nitrotyrosine-containing proteins were tentatively identified from diabetic retina. The identified nitrotyrosine-containing proteins participate in a variety of processes including glucose metabolism, signal transduction, and transcription/translation. Among the nitrated proteins were insulin-responsive glucose transporter type 4 (GLUT-4), which has been implicated previously in the pathogenesis of diabetes mellitus; exocyst complex component Exo70, which functions in insulin-stimulated glucose uptake of GLUT-4-containing vesicles; and fibroblast growth factor receptor 2, which influences retinal vascularization via fibroblast growth factor signaling. Nitration of tyrosine phosphorylation sites were identified in five proteins, including GLUT-4, exocyst complex component Exo70, protein-tyrosine phosphatase eta, sensory neuron synuclein, and inositol trisphosphate receptor 3. Quantitation of nitration and phosphorylation at common tyrosine modification sites in GLUT-4 and protein-tyrosine phosphatase eta from diabetic and nondiabetic animals suggests that nitration reduced tyrosine phosphorylation approximately 2X in these proteins from diabetic retina. The present results provide new insights regarding tyrosine nitration and its potential role in the molecular mechanisms of diabetic retinopathy.

Dataset Information

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

Publications

Expression, distribution and function of kinin B<sub>1</sub> receptor in the rat diabetic retina.

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