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Updated: Jul 12, 2026
Retinal Pathophysiological Evaluation in a Rat Model
Published on: May 6, 2022
Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream
Norihiro Nagai1, Kanako Izumi-Nagai, Yuichi Oike
1Laboratory of Retinal Cell Biology, Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
Purpose:
To investigate the involvement of the renin-angiotensin system (RAS) and the nuclear factor (NF)-kappaB 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-kappaB 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-kappaB 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-kappaB 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-kappaB pathway to diabetes-induced retinal inflammation, providing a mechanistic reason for targeting AT1-R or NF-kappaB in the treatment of diabetic retinopathy.
Insights
The renin-angiotensin system (RAS) and NF-kappaB pathway significantly contribute to diabetic retinal inflammation. Targeting the AT1-R or NF-kappaB may offer new treatments for diabetic retinopathy.
Area of Science:
- Ophthalmology
- Endocrinology
- Molecular Biology
Background:
- Diabetic retinopathy is a leading cause of vision loss.
- Retinal inflammation plays a critical role in the pathogenesis of diabetic retinopathy.
- The renin-angiotensin system (RAS) and nuclear factor-kappaB (NF-kappaB) pathway are implicated in inflammatory processes.
Purpose of the Study:
- To investigate the involvement of the RAS and NF-kappaB pathway in diabetes-induced retinal inflammation.
- To explore the therapeutic potential of targeting these pathways in diabetic retinopathy.
Main Methods:
- C57BL/6 mice with induced diabetes were treated with AT1-R blockers (telmisartan, valsartan), an AT2-R blocker (PD123319), or an NF-kappaB inhibitor (DHMEQ).
- Retinal expression of RAS components, ICAM-1, and VEGF were analyzed using RT-PCR and Western blot.
- Leukocyte adhesion and NF-kappaB activation were assessed in vivo and in vitro.
Main Results:
- Diabetes increased retinal RAS components and inflammation markers (ICAM-1, VEGF).
- AT1-R blockade and NF-kappaB inhibition significantly reduced retinal inflammation and leukocyte adhesion.
- In vitro studies confirmed that ARB suppressed glucose-induced NF-kappaB activation and inflammatory gene expression.
Conclusions:
- The AT1-R/NF-kappaB pathway is a significant contributor to diabetes-induced retinal inflammation.
- Targeting AT1-R or NF-kappaB presents a promising mechanistic approach for treating diabetic retinopathy.
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