title: Neuroprotective effects of angiotensin II type 1 receptor (AT1R) blocker, telmisartan, via modulating AT1R and AT2R signaling in retinal inflammation.
abstract: OBJECTIVE
  To investigate the retinal neural damage that occurs during inflammation and the therapeutic effects of the angiotensin II type 1 receptor (AT1R) blocker, telmisartan, using a model of endotoxin-induced uveitis (EIU).
  
  
  METHODS
  The localization of AT1R and AT2R was shown by immunohistochemistry. EIU was induced by intraperitoneal injection of lipopolysaccharide (LPS). Animals were treated with telmisartan for 2 days and were evaluated 24 hours later. Expression levels of angiotensin II, STAT3 activation induced by inflammatory cytokines, and retinal proteins essential for neural activities (e.g., synaptophysin, rhodopsin) were analyzed by immunoblot. An AT2R antagonist was administered to evaluate the contribution of AT2R signaling in this therapy. Dark-adapted full-field electroretinography (ERG) was also performed.
  
  
  RESULTS
  AT1R and AT2R were expressed in presynaptic terminals in most of the retinal neurons. AT1R was also expressed in Müller glial cells. During inflammation, angiotensin II expression was elevated, STAT3 was activated, and synaptophysin and rhodopsin expression were reduced. The expression of glial fibrillary acidic protein (GFAP), downstream of STAT3 activation, was induced in Müller glial cells. However, treatment with telmisartan successfully avoided all these changes. An AT2R antagonist lowered synaptophysin expression despite the treatment. STAT3 activity was negatively correlated with rhodopsin expression. Furthermore, ERG responses, which were mostly prevented by telmisartan, were disturbed during inflammation.
  
  
  CONCLUSIONS
  Retinal protein expression and visual function are both disturbed by inflammation. Treatment with the AT1R blocker telmisartan efficiently prevented these signs of retinal neural damage through the reduction of local angiotensin II expression, the blockade of AT1R, and the relative upregulation of AT2R function.
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kurihara
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ozawa
authors.forename: Kei
authors.initials: K
authors.lastname: Shinoda
authors.forename: Norihiro
authors.initials: N
authors.lastname: Nagai
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tsubota
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishida
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001565:Benzoates / Q000627:therapeutic use*; D003623:Dark Adaptation; D004195:Disease Models, Animal; D004596:Electroretinography; D019084:Fluorescent Antibody Technique, Indirect; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D015151:Immunoblotting; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D012243:Rhodopsin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D000077333:Telmisartan; D014605:Uveitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D050796:STAT3 Transcription Factor; D016708:Synaptophysin; D012243:Rhodopsin; D000077333:Telmisartan