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Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-kappaB pathway.
Invest Ophthalmol Vis Sci. 2007 Sep; 48(9):4342-50.IO

Abstract

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.

Authors+Show Affiliations

Laboratory of Retinal Cell Biology, Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17724226

Citation

Nagai, Norihiro, et al. "Suppression of Diabetes-induced Retinal Inflammation By Blocking the Angiotensin II Type 1 Receptor or Its Downstream Nuclear factor-kappaB Pathway." Investigative Ophthalmology & Visual Science, vol. 48, no. 9, 2007, pp. 4342-50.
Nagai N, Izumi-Nagai K, Oike Y, et al. Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-kappaB pathway. Invest Ophthalmol Vis Sci. 2007;48(9):4342-50.
Nagai, N., Izumi-Nagai, K., Oike, Y., Koto, T., Satofuka, S., Ozawa, Y., Yamashiro, K., Inoue, M., Tsubota, K., Umezawa, K., & Ishida, S. (2007). Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-kappaB pathway. Investigative Ophthalmology & Visual Science, 48(9), 4342-50.
Nagai N, et al. Suppression of Diabetes-induced Retinal Inflammation By Blocking the Angiotensin II Type 1 Receptor or Its Downstream Nuclear factor-kappaB Pathway. Invest Ophthalmol Vis Sci. 2007;48(9):4342-50. PubMed PMID: 17724226.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-kappaB pathway. AU - Nagai,Norihiro, AU - Izumi-Nagai,Kanako, AU - Oike,Yuichi, AU - Koto,Takashi, AU - Satofuka,Shingo, AU - Ozawa,Yoko, AU - Yamashiro,Kenji, AU - Inoue,Makoto, AU - Tsubota,Kazuo, AU - Umezawa,Kazuo, AU - Ishida,Susumu, PY - 2007/8/29/pubmed PY - 2007/10/12/medline PY - 2007/8/29/entrez SP - 4342 EP - 50 JF - Investigative ophthalmology & visual science JO - Invest Ophthalmol Vis Sci VL - 48 IS - 9 N2 - 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. SN - 0146-0404 UR - https://www.unboundmedicine.com/medline/citation/17724226/Suppression_of_diabetes_induced_retinal_inflammation_by_blocking_the_angiotensin_II_type_1_receptor_or_its_downstream_nuclear_factor_kappaB_pathway_ L2 - https://iovs.arvojournals.org/article.aspx?doi=10.1167/iovs.06-1473 DB - PRIME DP - Unbound Medicine ER -