title: Suppression of ocular inflammation in endotoxin-induced uveitis by blocking the angiotensin II type 1 receptor.
abstract: OBJECTIVE
  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 mug 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.
authors.affiliation: Laboratory of Retinal Cell Biology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Nagai
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
authors.forename: Kousuke
authors.initials: K
authors.lastname: Noda
authors.forename: Takashi
authors.initials: T
authors.lastname: Urano
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kubota
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ozawa
authors.forename: Hajime
authors.initials: H
authors.lastname: Shinoda
authors.forename: Takashi
authors.initials: T
authors.lastname: Koto
authors.forename: Kei
authors.initials: K
authors.lastname: Shinoda
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tsubota
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamashiro
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishida
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001082:Aqueous Humor / Q000166:cytology / Q000378:metabolism; D001562:Benzimidazoles / Q000627:therapeutic use*; D001565:Benzoates / Q000627:therapeutic use*; D015153:Blotting, Western; D002448:Cell Adhesion; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D005136:Eye Proteins / Q000378:metabolism; D007124:Immunoenzyme Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077333:Telmisartan; D015854:Up-Regulation; D014605:Uveitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D005136:Eye Proteins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D018799:Intercellular Adhesion Molecule-1; D000077333:Telmisartan