Prevention of photoreceptor apoptosis by activation of the glucocorticoid receptor.
OBJECTIVE
Evidence has accumulated that excessive light exposure may promote age-related and inherited retinal degeneration, in which photoreceptor death by apoptosis leads to loss of vision. In the current study, the effect of elevated corticosteroid levels on light-induced apoptosis of photoreceptors was determined.


METHODS
Photoreceptor apoptosis was induced in retinas of BALB/c mice by exposure to diffuse white light. High levels of corticosteroids were induced, either endogenously (fasting-mediated stress) or by a single intraperitoneal injection of dexamethasone (DEX). Photoreceptor damage was assessed morphologically and by electroretinography. Glucocorticoid receptor (GR) and activator protein (AP)-1 activities were shown by Western blot analysis and electrophoretic mobility shift assay (EMSA) of retinal nuclear extracts.


RESULTS
Fasting and injection of DEX led to an activation of GR in the retina, as judged by its translocation to the nucleus of retinal cells. On induction of GR activity before light exposure, AP-1 activity, normally induced by damaging doses of light, remained at basal levels. Both treatments completely prevented photoreceptor apoptosis and preserved retinal function.


CONCLUSIONS
Activity of the transcription factor AP-1 is associated with light-induced apoptosis. In the current study, pharmacologic suppression of AP-1 activity protected against light damage. Inhibition of AP-1 activity may have occurred by the protein-protein interaction of GR and AP-1.
Wenzel
A
A
Laboratory of Retinal Cell Biology, University Hospital Zurich, Zürich, Switzerland. awenzel@opht.unizh.ch
Grimm
C
C
Seeliger
M W
MW
Jaissle
G
G
Hafezi
F
F
Kretschmer
R
R
Zrenner
E
E
Remé
C E
CE
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D015153:Blotting, Western; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D004596:Electroretinography; D005508:Food Deprivation; D005938:Glucocorticoids / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008027:Light / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D011833:Radiation Injuries, Experimental / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012162:Retinal Degeneration / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D003907:Dexamethasone; D003345:Corticosterone