Induction of endoplasmic reticulum stress genes, BiP and chop, in genetic and environmental models of retinal degeneration.
OBJECTIVE
Endoplasmic reticulum (ER) stress has been observed in animal models of retinitis pigmentosa expressing P23H rhodopsin. We compared levels of tightly induced ER stress genes, Binding of immunoglobulin protein (BiP) and CCAAT/enhancer-binding protein homologous protein (Chop), in seven additional models of retinal degeneration arising from genetic or environmental causes.


METHODS
Retinas from transgenic S334ter rhodopsin (lines 3, 4, and 5) and Royal College of Surgeons (RCS and RCS-p+) rats from postnatal (P) days 10 to 120 were analyzed. In a constant light (CL) model of retinal degeneration, BALB/c mice were exposed to 15,000 lux of CL for 0 to 8 hours. Retinal tissues from three to eight animals per experimental condition were collected for histologic and molecular analyses.


RESULTS
S334ter animals revealed significant increases in BiP, S334ter-3 (3.3× at P15), S334ter-4 (4× at P60), and S334ter-5 (2.2× at P90), and Chop, S334ter-3 (1.3× at P15), S334ter-4 (1.5× at P30), and S334ter-5 (no change), compared with controls. P23H-3 rats showed significant increase of BiP at P60 (2.3×) and Chop (1.6×). RCS and RCS-p+ rats showed significant increases in BiP at P60 (2.4×) and P20 (1.8×), respectively, but no statistically significant changes in Chop. BALB/c mice showed increases in BiP (1.5×) and Chop (1.3×) after 4 hours of CL. Increased levels of these ER stress markers correlated with photoreceptor cell loss.


CONCLUSIONS
Our study reveals surprising increases in BiP and to a lesser degree Chop in retinal degenerations arising from diverse causes. We propose that manipulation of ER stress responses may be helpful in treating many environmental and heritable forms of retinal degeneration.
Department of Pathology, University of California, San Diego, La Jolla, California, USA.
Heike
H
Kroeger
Carissa
C
Messah
Kelly
K
Ahern
Jason
J
Gee
Victory
V
Joseph
Michael T
MT
Matthes
Douglas
D
Yasumura
Marina S
MS
Gorbatyuk
Wei-Chieh
WC
Chiang
Matthew M
MM
LaVail
Jonathan H
JH
Lin
D000818:Animals; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D004781:Environmental Exposure / Q000009:adverse effects; D005786:Gene Expression Regulation; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000096:biosynthesis / Q000235:genetics*; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000235:genetics*; D051028:bcl-2-Associated X Protein
C539791:Bax-inhibiting peptide, BIP; D009842:Oligopeptides; D051028:bcl-2-Associated X Protein; D051742:Transcription Factor CHOP; D012313:RNA; D012243:Rhodopsin