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Anti-inflammatory effect of angiotensin type 1 receptor antagonist on endotoxin-induced uveitis in rats

  • Inflammatory Disorders
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Abstract

Background

Angiotensin II type 1 (AT1) receptor-antagonists are widely used for treatment of hypertension. Recent studies have demonstrated a protective effect of renin angiotensin system (RAS) antagonism against immune-mediated inflammatory diseases such as myocarditis, chronic allograft rejection, antiglomerular basement membrane nephritis, colitis, and arthritis. However, only a few reports have demonstrated the effect of RAS in ocular inflammatory conditions. The purpose of this study was to investigate the anti-inflammatory effect of a selective AT1 receptor antagonist, losartan, on endotoxin-induced uveitis (EIU) and compare the effect on experimental autoimmune uveoretinitis (EAU).

Methods

To induce EIU, 7-week-old Lewis rats were injected subcutaneously with 200 μg lipopolysaccharide (LPS). Losartan was administered intravenously at the same time. The aqueous humor was collected from eyes 24 h after LPS injection. The number of infiltrating cells, protein concentration, and levels of tumor necrosis factor (TNF)-α and monocyte chemoattractant protein-1 (MCP-1) in the aqueous humor were determined. The collected eyes were immunohistochemically stained with monoclonal antibody for activated nuclear factor (NF)-κB. To induce EAU, C57BL/6 mice (6–8 weeks old) were immunized with human interphotoreceptor retinoid binding protein (hIRBP)-derived peptide emulsified in complete Freund’s adjuvant (CFA) and concomitantly injected with purified Bordetella pertussis toxin (PTX). Clinical severity of EAU and T cell proliferative response were analyzed.

Results

Losartan significantly suppressed the development of EIU. Numbers of aqueous cells of control EIU rats, those from EIU rats treated with 1 or 10 mg/kg of losratan were 75.3 ± 45.6 × 105, 27.9 ± 8.1 × 105, or 41.3 ± 30.9 × 105 cells/ml respectively (p < 0.01 vs control). Aqueous protein, TNF-α, and MCP-1 levels were also significantly decreased in a manner dependent on the amount of losartan administered (p < 0.01). Treatment of EIU rats with losartan suppressed activation of NF-κB at the iris ciliary body. Thus, the suppressive effect of losartan on ocular inflammation in EIU appeared to result from down-regulation of NF-κB activation and reduction of inflammatory cytokine production. On the other hand, in the EAU model, neither the clinical score nor the antigen-specific T cell proliferative response was significantly influenced by the treatment with losartan.

Conclusions

The present findings indicate that RAS may be involved in the acute inflammation of the eye, but not in T cell-dependent ocular autoimmunity. Antagonism of the RAS may be a potential prophylactic strategy for treatment of the human acute ocular inflammation.

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Acknowledgements

This work was supported in part by Grants-in-Aid for Scientific Research (S), (B) and (C) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, by Grant-in-Aid for Scientific Research on Priority Areas from MEXT Japan, and by a Grant for Researches on Sensory and Communicative Disorders, Ministry of Health, Labour and Welfare, Japan.

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Authors and Affiliations

  1. Department of Ophthalmology and Visual Sciences, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    Akiko Miyazaki, Nobuyoshi Kitaichi, Kazuhiro Ohgami, Daiju Iwata, Xue-Hai Jin & Shigeaki Ohno

  2. Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan

    Akiko Miyazaki, Kazuya Iwabuchi & Kazunori Onoé

  3. Department of Gastroenterology, Omori Red Cross Hospital, Tokyo, Japan

    Taiki Morohashi

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  1. Akiko Miyazaki
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Correspondence to Kazunori Onoé.

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Miyazaki, A., Kitaichi, N., Ohgami, K. et al. Anti-inflammatory effect of angiotensin type 1 receptor antagonist on endotoxin-induced uveitis in rats. Graefes Arch Clin Exp Ophthalmol 246, 747–757 (2008). https://doi.org/10.1007/s00417-007-0730-2

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