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(Investigative Ophthalmology and Visual Science. 2007;48:4342-4350.)
© 2007 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.06-1473
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Suppression of Diabetes-Induced Retinal Inflammation by Blocking the Angiotensin II Type 1 Receptor or Its Downstream Nuclear Factor-{kappa}B Pathway

Norihiro Nagai,1,2,3 Kanako Izumi-Nagai,1,2,3 Yuichi Oike,1,4 Takashi Koto,1,2 Shingo Satofuka,1,2 Yoko Ozawa,1,2 Kenji Yamashiro,5 Makoto Inoue,2 Kazuo Tsubota,2 Kazuo Umezawa,6 and Susumu Ishida1,2

1From 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)-{kappa}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-{kappa}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-{kappa}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-{kappa}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-{kappa}B pathway to diabetes-induced retinal inflammation, providing a mechanistic reason for targeting AT1-R or NF-{kappa}B in the treatment of diabetic retinopathy.




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