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S. Satofuka, A. Ichihara, N. Nagai, K. Noda, Y. Ozawa, A. Fukamizu, K. Tsubota, H. Itoh, Y. Oike, S. Ishida; (Pro)renin Receptor-Mediated Signal Transduction and Tissue Renin-Angiotensin System Contribute to Diabetes-Induced Retinal Inflammation. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5380.
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© ARVO (1962-2015); The Authors (2016-present)
Receptor-associated prorenin system (RAPS) refers to the pathogenic mechanisms whereby prorenin binding to its receptor dually activates tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling via the receptor. The aim of the present study was to define the association of RAPS with diabetes-induced retinal inflammation.
Long-Evans rats, C57BL/6 mice or angiotensin II type 1 receptor (AT1-R)-deficient mice with streptozotocin-induced diabetes were treated with (pro)renin receptor blocker (PRRB). Retinal mRNA expression of prorenin and (pro)renin receptor was examined by quantitative RT-PCR. Leukocyte adhesion to the retinal vasculature was evaluated with a concanavalin A lectin perfusion-labeling technique. Retinal protein levels of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule (ICAM)-1 were examined by ELISA. Retinal ERK activation was analyzed by western blotting.
Induction of diabetes led to significant increase in retinal expression of prorenin, but not (pro)renin receptor. Retinal adherent leukocytes were significantly suppressed with PRRB. Administration of PRRB inhibited diabetes-induced retinal expression of VEGF and ICAM-1. To clarify the role of signal transduction via (pro)renin receptor in the diabetic retina, we utilized AT1-R-deficient mice in which RAS was deactivated. Retinal adherent leukocytes in AT1-R-deficient diabetic mice were significantly suppressed with PRRB. PRRB suppressed the activation of ERK and the production of VEGF, but not ICAM-1, in AT1-R-deficient diabetic mice.
These results indicate significant contribution of RAPS to the pathogenesis of diabetes-induced retinal inflammation, suggesting the possibility of (pro)renin receptor as a novel, molecular target for the treatment of diabetic retinopathy.
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