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Jonathan H. Lin, Heike Kroeger, Carissa Messah, Kelly Ahern, Jason Gee, Victory Joseph, Michael T. Matthes, Douglas Yasumura, Marina S. Gorbatyuk, Matthew M. LaVail; Endoplasmic Reticulum Stress In Environmental And Genetic Models Of Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4275.
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Endoplasmic reticulum (ER) stress has been observed in animal models of retinitis pigmentosa arising from P23H rhodopsin. We asked if ER stress was found in other models of retinal degeneration arising from environmental or genetic causes. We measured ER stress levels in mice in a constant light (CL)-induced model of retinal degeneration; in transgenic rats expressing mutant S334ter rhodopsin; and in Royal College of Surgeons (RCS) rats bearing mutant Mertk.
BALB/c albino mice were exposed to 15,000 lux of fluorescent CL for 0,1,2,4, or 8 hours. S334ter transgenic rats (lines 3, 4, and 5), RCS and RCS-p+ rats with inherited retinal dystrophy were collected at postnatal (P) days 10, 12, 20, 30, 40, 60, 90, and 120. Retinal tissues from 3-10 animals per experimental condition were collected for histologic and molecular analyses to quantify retinal degeneration and mRNA levels of two well-studied ER stress-induced genes, BiP and Chop.
BALB/c mice revealed 1.5x (P=0.0324) more BiP and 1.3x (P=0.0285) more Chop mRNA levels after 4 hours of CL. These findings correlated with photoreceptor layer cell loss by histology. S334ter-3 retinas revealed 3.3x (P=1E-06) more BiP and 1.3x (P=0.03) more Chop mRNA levels at P15; S334ter-4 showed 4x (P=9E-06) more BiP mRNA at P60 and 1.5x (P=0.005) more Chop mRNA at P30; retinal tissue from S334ter-5 had 2.2x (P=0.008) more BiP mRNA at P90, but no significant increase in Chop mRNA was found when compared to age-matched controls. P23H-3 rats demonstrated 2.3x (P=0.0048) more BiP mRNA levels and 1.6x (P=0.0073) more Chop mRNA levels at P60 compared to controls. RCS and RCS-p+ rats showed a significant increase of BiP mRNA at 2.4x at P60 and 1.8x at P20, respectively (RCS, P=0.0006; RCS-p+, P=0.005) without changes in Chop mRNA levels.
Our study revealed statistically significant increases in ER stress markers BiP in CL-induced retinal degeneration, S334ter rats, P23H rats, and RCS rats; and Chop in CL-induced retinal degeneration, two S334ter rat lines, and P23H rats. Increase in ER stress correlated with histologic evidence of retinal degeneration in all models. We propose that manipulation of ER stress responses may be helpful in treating many environmental and heritable forms of retinal degeneration.
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