Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-κB pathway

Norihiro Nagai, Kanako Izumi-Nagai, Yuichi Oike, Takashi Koto, Shingo Satofuka, Yoko Ozawa, Kenji Yamashiro, Makoto Inoue, Kazuo Tsubota, Kazuo Umezawa, Susumu Ishida

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

PURPOSE. To investigate the involvement of the renin-angiotensin system (RAS) and the nuclear factor (NF)-κB 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-κB 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-κB 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-κB 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-κB pathway to diabetes-induced retinal inflammation, providing a mechanistic reason for targeting AT1-R or NF-κB in the treatment of diabetic retinopathy.

Original languageEnglish
Pages (from-to)4342-4350
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume48
Issue number9
DOIs
Publication statusPublished - 2007 Sep

Fingerprint

Angiotensin Type 1 Receptor
Intercellular Adhesion Molecule-1
Inflammation
Renin-Angiotensin System
Chemokine CCL2
Valsartan
Angiotensin II
Vascular Endothelial Growth Factor A
Leukocytes
Angiotensin II Type 1 Receptor Blockers
Glucose
Polymerase Chain Reaction
Messenger RNA
Diabetic Retinopathy
Concanavalin A
Inbred C57BL Mouse
Lectins
Retina
Proteins
Up-Regulation

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-κB pathway. / Nagai, Norihiro; Izumi-Nagai, Kanako; Oike, Yuichi; Koto, Takashi; Satofuka, Shingo; Ozawa, Yoko; Yamashiro, Kenji; Inoue, Makoto; Tsubota, Kazuo; Umezawa, Kazuo; Ishida, Susumu.

In: Investigative Ophthalmology and Visual Science, Vol. 48, No. 9, 09.2007, p. 4342-4350.

Research output: Contribution to journalArticle

Nagai, Norihiro ; Izumi-Nagai, Kanako ; Oike, Yuichi ; Koto, Takashi ; Satofuka, Shingo ; Ozawa, Yoko ; Yamashiro, Kenji ; Inoue, Makoto ; Tsubota, Kazuo ; Umezawa, Kazuo ; Ishida, Susumu. / Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-κB pathway. In: Investigative Ophthalmology and Visual Science. 2007 ; Vol. 48, No. 9. pp. 4342-4350.
@article{b1fb88948c0c49168f94738389c0a889,
title = "Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-κB pathway",
abstract = "PURPOSE. To investigate the involvement of the renin-angiotensin system (RAS) and the nuclear factor (NF)-κB 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-κB 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-κB 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-κB 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-κB pathway to diabetes-induced retinal inflammation, providing a mechanistic reason for targeting AT1-R or NF-κB in the treatment of diabetic retinopathy.",
author = "Norihiro Nagai and Kanako Izumi-Nagai and Yuichi Oike and Takashi Koto and Shingo Satofuka and Yoko Ozawa and Kenji Yamashiro and Makoto Inoue and Kazuo Tsubota and Kazuo Umezawa and Susumu Ishida",
year = "2007",
month = "9",
doi = "10.1167/iovs.06-1473",
language = "English",
volume = "48",
pages = "4342--4350",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "9",

}

TY - JOUR

T1 - Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-κB 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 - 2007/9

Y1 - 2007/9

N2 - PURPOSE. To investigate the involvement of the renin-angiotensin system (RAS) and the nuclear factor (NF)-κB 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-κB 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-κB 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-κB 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-κB pathway to diabetes-induced retinal inflammation, providing a mechanistic reason for targeting AT1-R or NF-κB in the treatment of diabetic retinopathy.

AB - PURPOSE. To investigate the involvement of the renin-angiotensin system (RAS) and the nuclear factor (NF)-κB 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-κB 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-κB 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-κB 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-κB pathway to diabetes-induced retinal inflammation, providing a mechanistic reason for targeting AT1-R or NF-κB in the treatment of diabetic retinopathy.

UR - http://www.scopus.com/inward/record.url?scp=35148898712&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35148898712&partnerID=8YFLogxK

U2 - 10.1167/iovs.06-1473

DO - 10.1167/iovs.06-1473

M3 - Article

VL - 48

SP - 4342

EP - 4350

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 9

ER -