Increased light damage susceptibility at night does not correlate with RPE65 levels and rhodopsin regeneration in rats
Introduction
Light absorption by the visual pigment rhodopsin is required to initiate the phototransduction cascade (Pepe, 2001). Absorption of excessive amounts of light, however, may eventually lead to photoreceptor degeneration by an apoptotic process (Grimm et al., 2000b, Remé et al., 1998). Increasing epidemiological and experimental evidence suggests that light may be an important exogenous co-factor for the development and severity of retinal degenerations as they occur during the course of age related macular degeneration (AMD) and retinitis pigmentosa (RP) (Cideciyan et al., 1998, Cruickshanks et al., 1993, Cruickshanks et al., 2001, Simons, 1993, Taylor et al., 1990). In addition, the progression of retinal degeneration is enhanced by light in an increasing number of animal models for human retinal diseases (Chen et al., 1999a, Chen et al., 1999b, LaVail et al., 1999, Organisciak et al., 1999, Sanyal and Hawkins, 1986, Wang et al., 1997). Light damage susceptibility is at least partially controlled by genetic factors in different mouse strains (LaVail et al., 1987a). One factor has been identified as a sequence variation in the Rpe65 gene (Danciger et al., 2000). The variation was shown to influence steady-state levels of the RPE65 protein in the mouse and to correlate with rhodopsin regeneration kinetics in the visual cycle (Wenzel et al., 2001). RPE65 is specifically expressed in the pigment epithelium (Seeliger et al., 2001) and is essential for the re-isomerization of all-trans retinal during the visual cycle and thus for the regeneration of rhodopsin after bleaching (Redmond et al., 1998). Rhodopsin regeneration is an important factor determining light damage susceptibility in different mouse strains (Wenzel et al., 2001). Inhibition of the visual cycle leads to strong protection against light-induced photoreceptor apoptosis (Keller et al., 2001). Strain differences in light damage susceptibility have been observed also in rats (Borges et al., 1990, Iseli et al., 2002). However, in rats, RPE65 protein and rhodopsin regeneration do not seem to be the main determinants for the observed strain differences (Iseli et al., 2002) suggesting that other genetic factors may determine damage after light exposure in different rat strains. Furthermore, as an exogenous component determining damage susceptibility, a photostatic adjustment to environmental illuminance levels was found (Penn and Williams, 1986). It has been shown that light damage susceptibility in a specific rat strain varies with the time of day (Duncan and O'Steen, 1985, Organisciak et al., 2000, White and Fisher, 1987). The mechanism for this observation is unclear but may involve a diurnal/circadian-dependent expression of intrinsic factor(s). For example a rhythmic variation of molecules involved in phototransduction was observed (Brann and Cohen, 1987, Farber et al., 1991, Korenbrot and Fernald, 1989, McGinnis et al., 1992, Organisciak et al., 1991, Tosini and Menaker, 1996, Wiechmann and Sinacola, 1997). One of the factors might be RPE65 which may influence efficiency of rhodopsin regeneration during day- or night-time. Therefore, we tested expression of the Rpe65 gene during night and day and analyzed potential effects on rhodopsin regeneration and light damage susceptibility.
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Animals and rearing conditions
All procedures concerning animals adhered to the ARVO statement for the use of animals in ophthalmic and vision research. Albino rats (Sprague–Dawly) were purchased and reared for additional 10–15 days in a light/dark cycle (lights on: 6 a.m., lights off: 6 p.m.) with 60–100 lux within the cages. Experiments were performed at the age of 6–8 weeks. Water and rodent food were provided ad libitum. Animals that were exposed at midnight were taken from the regular light-dark cycle. Therefore, these
Increased light damage susceptibility at night
Earlier work has shown that susceptibility to light damage varies with the time of day (Duncan and O'Steen, 1985, Organisciak et al., 2000, White and Fisher, 1987). In most of these experiments repetitive light exposure over several days had been used (Duncan and O'Steen, 1985, White and Fisher, 1987), or light damage was induced with green light (Organisciak et al., 2000). Therefore, we verified a diurnal dependent light damage susceptibility in our system by exposing albino rats at noon or at
Discussion
Light damage susceptibility is increased during the night in animals kept under a light–dark cycle of 12 hr:12 hr (Organisciak et al., 2000). Here we tested whether this difference might correlate with levels of RPE65 protein and/or rhodopsin regeneration. These two parameters have recently been shown to correlate with light damage susceptibility in different mouse strains (Wenzel et al., 2001). We show that in rats, Rpe65 gene expression, RPE65 protein levels and rhodopsin regeneration do not
Acknowledgements
The authors like to thank Coni Imsand, Dora Greuter and Gabi Hoegger for skilled technical assistance and Ulli Busse for administrative help. This work was supported by the Swiss National Science Foundation, the Bruppacher Foundation, the German Research Council and the Velux Foundation.
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