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B Pathway1From the Laboratory of Retinal Cell Biology, the 2Department of Ophthalmology, and the 4Laboratory of Vascular Biology and Metabolism, Keio University School of Medicine, Tokyo, Japan; the 5Department of Ophthalmology, Kobe City General Hospital, Kobe, Japan; and the 6Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Japan.
PURPOSE. To investigate the involvement of the renin-angiotensin system (RAS) and the nuclear factor (NF)-
B pathway with diabetes-induced retinal inflammation.
METHODS. Six weeks after induction of diabetes, C57BL/6 mice were treated with the angiotensin II type 1 receptor (AT1-R) blocker (ARB) telmisartan or valsartan, the AT2-R blocker PD123319, or the NF-B inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) daily for 1 week. Retinal mRNA and protein levels of the RAS components were examined by RT-PCR and Western blot, respectively. Leukocyte adhesion to the retinal vasculature was evaluated with a concanavalin A lectin perfusion-labeling technique. Retinal expression levels of intercellular adhesion molecule (ICAM)-1 and vascular endothelial growth factor (VEGF) were examined by RT-PCR and ELISA. ARB or DHMEQ was applied to murine capillary endothelial (b-End3) cells stimulated with a high concentration of glucose to analyze nuclear translocation of NF-B via immunohistochemistry for p65 and mRNA and protein levels of ICAM-1 and monocyte chemotactic protein (MCP)-1.
RESULTS. Induction of diabetes led to a significant increase in retinal expression and production of the RAS components including angiotensin II, AT1-R, and AT2-R. Retinal adherent leukocytes were significantly suppressed by AT1-R, but not by AT2-R, blockade. Administration of the ARB, but not of PD123319, inhibited diabetes-induced retinal expression of ICAM-1 and VEGF. DHMEQ also suppressed these cellular and molecular inflammatory parameters in the diabetic retina to the levels obtained with ARB treatment. In vitro, glucose-induced nuclear translocation of NF-B p65 and upregulation of ICAM-1 and MCP-1 were significantly suppressed by application of the ARB. The in vivo treatment with the ARB, as well as DHMEQ, attenuated the diabetes-induced retinal expression of angiotensin II and AT1-R, per se.
CONCLUSIONS. The present data revealed significant a contribution of the AT1-R/NF-B pathway to diabetes-induced retinal inflammation, providing a mechanistic reason for targeting AT1-R or NF-B in the treatment of diabetic retinopathy.
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