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animals, whereas no significant increase was observed between light (–) and light
(+) animals in the wt-SFO group (Tanito et al. 2009).
65.4 Discussion
The fat-1 transgene encodes an n3 fatty acid desaturase that converts n6 to n3 PUFA (Spychalla et al. 1997; Kang et al. 2004). In this study, we demonstrated that expression of the fat-1 transgene enables mice fed an n3-deficient diet to endogenously synthesize and incorporate n3 fatty acids into ROS membranes (as well as other tissues), resulting in significantly lower n6/n3 ratios (Figs. 65.1 and 65.2).
The functional and morphological analyses in the light-damage experiments revealed that retinas from animals with low n6/n3 ratios (i.e., fat-1-SFO) were severely damaged. Several previous studies using dietary deprivation of n3 PUFA in albino rats have reported a positive relationship between n3-PUFA levels and susceptibility to light damage (Bush et al. 1991; Koutz et al. 1995; Organisciak et al. 1996). Our results strongly suggest that the levels of n3 PUFA are related to the vulnerability of the retina to photooxidative stress.
Due to facile reactivity with histidine, cysteine, or lysine residues of proteins (Uchida and Stadtman 1992), the reactive aldehydes exhibit a variety of cytopathological effects such as inhibition of enzyme activity; inhibition of protein, RNA, and DNA synthesis; cell cycle arrest; and apoptosis (Toyokuni 1999; Awasthi et al. 2004). Our earlier work suggests that modifications by lipid aldehydes of a specific set of retinal proteins are molecular events that precede light-induced photoreceptor cell apoptosis (Tanito et al. 2005, 2006b). Collectively, with the morphological and functional analyses, current results strongly suggest causal relationships between n3 PUFA levels, n3 PUFA oxidation, and the vulnerability of the retina to photooxidative stress.
The long chain PUFA DHA is more abundant in ROS than in any other mammalian membrane (Fliesler and Anderson 1983) and photoreceptors have a robust mechanism to conserve it (Wiegand et al. 1991). We showed a number of years ago that the fatty acid composition of ROS membranes is an important determinant for optimal retinal function in rodents (Benolken et al. 1973; Wheeler et al. 1975) and DHA deficiency results in the reduction of ERG response, with a-wave amplitudes affected more profoundly.
The roles of DHA in the retina are potentially conflicting in the literature. In the present study, we provide clear evidence that fat-1-SFO mice are more susceptible to light damage than wt-SFO mice and that the levels of DHA, the major n3 PUFA in the retina, and protein modifications by its oxidation products 4-HHE, are positively related to the vulnerability. These results highlight the ying and yang roles of n3 PUFA and DHA in retinal physiology and pathology.
Acknowledgments Financial support from the Foundation Fighting Blindness, Research to Prevent Blindness, Inc., the National Eye Institute (EY12190, EY04149, and EY00871), and National Center for Research Resources (RR17703) is gratefully acknowledged.
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Chapter 66
Activation of Müller Cells Occurs During
Retinal Degeneration in RCS Rats
Tong Tao Zhao, Chun Yu Tian, and Zheng Qin Yin
Abstract Müller cells can be activated and included in different functions under many kinds of pathological conditions, however, the status of Müller cells in retinitis pigmentosa are still unknown. Using immunohistochemisty, Western blots and co-culture, we found that Müller cells RCS rats, a classic model of RP, could be activated during the progression of retinal degeneration. After being activated at early stage, Müller cells began to proliferate and hypertrophy, while at later stages, they formed a local ‘glial seal’ in the subretinal space. As markers of Müller cells activation, the expression of GFAP and ERK increased significantly with progression of retinal degeneration. Co-cultures of normal rat Müller cells and mixed RCS rat retinal cells show that Müller cells significantly increase GFAP and ERK in response to diffusable factors from the degenerting retina, which implies that Müller cells activation is a secondary response to retinal degeneration.
66.1 Introduction
Retinal degeneration is a group of severe diseases leading to blindness, which lack effective therapeutic measures. Among the retinal degenerative diseases, retinitis pigmentosa is the most common inherited retinal disease, and features a progressive apoptosis of photoreceptors and dysfunction of the retinal pigmented epithelium (RPE) (Lund et al., 2001).
Z.Q. Yin (B)
Southwest Hospital, Southwest Eye Hospital, Third Military Medical University, Chongqing, 400038, China
e-mail: qinzyin@yahoo.com.cn
The authors Tong Tao Zhao and Zheng Qin Yin contributed equally to this work.
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Medicine and Biology 664, DOI 10.1007/978-1-4419-1399-9_66,C Springer Science+Business Media, LLC 2010