Blockade of endothelinergic receptors prevents development of proliferative vitreoretinopathy in mice.
Proliferative vitreoretinopathy (PVR) is characterized by severe glial remodeling. Glial activation and proliferation that occur in brain diseases are modulated by endothelin-1 (ET-1) and its receptor B (ETR-B). Because retinal astrocytes contain ET-1 and express ETR-B, we studied the changes of these molecules in an experimental mouse model of PVR and in human PVR. Both ET-1 and ETR-B immunoreactivities increased in mouse retina after induction of PVR with dispase. Epi- and subretinal outgrowths also displayed these immunoreactivities in both human and experimental PVR. Additionally, myofibroblasts and other membranous cell types showed both ET-1 and ETR-B immunoreactivities. In early stages of experimentally induced PVR, prepro-ET-1 and ETR-B mRNA levels increased in the retina. These mRNA levels also increased after retinal detachment (RD) produced by subretinal injection. Treatment of mice with tezosentan, an antagonist of endothelinergic receptors, reduced the histopathological hallmarks of dispase-induced PVR: retinal folding, epiretinal outgrowth, and gliosis. Our findings in human and in dispase-induced PVR support the involvement of endothelinergic pathways in retinal glial activation and the phenotypic transformations that underlie the growth of membranes in this pathology. Elucidating these pathways further will help to develop pharmacological treatments to prevent PVR. In addition, the presence of ET-1 and ETR-B in human fibrous membranes suggests that similar treatments could be helpful after PVR has been established.
Iribarne
María
M
Facultad de Ciencias Biomédicas, Universidad Austral, Pilar, Buenos Aires, Argentina.
Ogawa
Liliana
L
Torbidoni
Vanesa
V
Dodds
Cristian M
CM
Dodds
Ricardo A
RA
Suburo
Angela M
AM
D000818:Animals; D010450:Endopeptidases; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007267:Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012163:Retinal Detachment / Q000378:metabolism / Q000473:pathology; D013777:Tetrazoles / Q000494:pharmacology; D018630:Vitreoretinopathy, Proliferative / Q000378:metabolism* / Q000473:pathology*
D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D005904:Glial Fibrillary Acidic Protein; D011725:Pyridines; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D013777:Tetrazoles; C120582:tezosentan; D010450:Endopeptidases; C023139:dispase