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(Investigative Ophthalmology and Visual Science. 2006;47:5545-5552.)
© 2006 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.06-0478
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Neuroprotective Effects of Angiotensin II Type 1 Receptor (AT1R) Blocker, Telmisartan, via Modulating AT1R and AT2R Signaling in Retinal Inflammation

Toshihide Kurihara,1,2,3,4 Yoko Ozawa,1,2,3,4 Kei Shinoda,5 Norihiro Nagai,1,3 Makoto Inoue,1 Yuichi Oike,3,6 Kazuo Tsubota,1 Susumu Ishida,1,3 and Hideyuki Okano2

1From the Departments of Ophthalmology, 2Physiology, and 6Cell Differentiation, and the 3Laboratory of Retinal Cell Biology, Keio University School of Medicine; and the 5Department of Ophthalmology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

PURPOSE. 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.




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