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(Investigative Ophthalmology and Visual Science. 2005;46:2925-2931.)
© 2005 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.04-1476
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Suppression of Ocular Inflammation in Endotoxin-Induced Uveitis by Blocking the Angiotensin II Type 1 Receptor

Norihiro Nagai,1,2,3 Yuichi Oike,1,3 Kousuke Noda,2 Takashi Urano,3 Yoshiaki Kubota,3 Yoko Ozawa,1,2 Hajime Shinoda,2 Takashi Koto,1 Kei Shinoda,2 Makoto Inoue,2 Kazuo Tsubota,2 Kenji Yamashiro,4 Toshio Suda,3 and Susumu Ishida1,2

1From the Laboratory of Retinal Cell Biology and the 2Departments of Ophthalmology and 3Cell Differentiation, Keio University School of Medicine, Tokyo, Japan; and the 4Department of Ophthalmology, Kobe City General Hospital, Kobe, Japan.

PURPOSE. To examine whether the angiotensin II type 1 receptor (AT1-R) signaling plays a role in ocular inflammation in endotoxin-induced uveitis (EIU).

METHODS. EIU was induced in C57BL/6 mice by a single intraperitoneal injection of 150 µg lipopolysaccharide (LPS). Tissue localization, mRNA expression, and protein levels of AT1-R in murine retinas were examined by immunohistochemistry, RT-PCR, and Western blot analyses, respectively. Telmisartan, an AT1-R antagonist widely used as an antihypertensive agent, was administered intraperitoneally at a dose of 10 mg/kg daily for 5 days until the injection of LPS. Twenty-four hours after administration, leukocyte adhesion to the retinal vasculature was evaluated with a concanavalin A lectin perfusion-labeling technique. Retinal mRNA and protein levels of intercellular adhesion molecule (ICAM)-1 were examined by RT-PCR and ELISA, respectively. Protein concentration and inflammatory cells in the aqueous humor were also measured.

RESULTS. Retinal vessels were positive for AT1-R. In mice with EIU, retinal AT1-R mRNA and protein levels were significantly increased when compared to the normal control. EIU animals also showed significant increases in the number of inflammatory cells infiltrating the anterior chamber and adhering to the retinal vessels and in retinal ICAM-1 levels. Administration of telmisartan to EIU mice resulted in significant suppression of retinal ICAM-1 expression and leukocyte adhesion and infiltration compared with vehicle treatment. Protein concentration in the aqueous humor of telmisartan-treated EIU mice tended to be lower than that of vehicle-treated EIU mice, but the difference was not statistically significant.

CONCLUSIONS. AT1-R signaling blockade inhibited retinal ICAM-1 upregulation and leukocyte adhesion and infiltration in the EIU model. These results suggest the potential use of an AT1-R antagonist as a therapeutic agent to reduce ocular inflammation.




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