Blockade of Endothelinergic Receptors and Prevention of PVR Lesions in the Dispase Model

IRIBARNE M; TORBIDONI V; SUBURO AM

Fort Lauderdale, Florida

Congreso; Association for Research in Vision and Ophthalmology (ARVO) 2008 Annual Meeting; 2008

ARVO

Purpose: Retinal detachment (RD) and proliferative vitreoretinopathy (PVR) are characterized by severe glial remodeling. Retinal astrocytes normally express and accumulate endothelin-1 (ET-1), a small peptide involved in glial activation and development of fibrotic conditions. Since astrocytes also express the endothelinergic receptor ETR-B, we tested the effect of tezosentan, a mixed endothelinergic antagonist, on PVR-like lesions induced by dispase intravitreal injection in miceMethods: Male C57BL/6J mice were anesthetized and injected intravitreally with 0.3 U/µl dispase. Under these conditions, retinal folds and PVR-like membranes develop within a week. Mice received daily injections of tezosentan (10 mg/kg, sc, Actelion Pharmaceuticals, Switzerland), or saline solution. Control and treated animals were euthanatized on day 3 and 7. Retinas were used for detection of prepro-ET-1 and ETR-B mRNAs by RT-PCR, or for immunochemical detection of ET-1, ETR-B and GFAP.Results: Retinal expression of prepro-ET-1 and ETR-B mRNAs significantly increased 3 days after dispase intravitreal injection. In these retinas, astrocytes displayed stronger ET-1 and ETR-B than in controls. Astrocyte processes apparently invaded the vitreal space through discontinuities of the inner limiting membrane (ILM). One week after dispase injection, control mice showed large retinal detachments, extensive folding of the retina and had epi- and subretinal membranes. By contrast, animals receiving tezosentan, showed minimal retinal folding. Few epiretinal membranes appeared in tezosentan-treated animals, but subretinal membranes were still present. Subretinal membranes lacked ETB-R immunoreactivity, whereas epiretinal membranes and the boundary between these membranes and the retina displayed strong ETB-R immunoreactivivity.Conclusions: The ILM and astrocytes were early affected by intravitreal dispase injections. Astrocytes increased expression of ET-1 and ETR-B and seemed to be the first retinal cells involved in vitreal outgrowths. Treatment with an endothelinergic antagonist blocked retinal folding and growth of epiretinal membranes. Subretinal membranes were not affected, probably because they lack ETR-B.