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mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice
Chen Zhao, … , Matthew M. LaVail, Douglas Vollrath
Chen Zhao, … , Matthew M. LaVail, Douglas Vollrath
Published December 6, 2010
Citation Information: J Clin Invest. 2011;121(1):369-383. https://doi.org/10.1172/JCI44303.
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Research Article Ophthalmology Article has an altmetric score of 4

mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice

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Abstract

Retinal pigment epithelial (RPE) cell dysfunction plays a central role in various retinal degenerative diseases, but knowledge is limited regarding the pathways responsible for adult RPE stress responses in vivo. RPE mitochondrial dysfunction has been implicated in the pathogenesis of several forms of retinal degeneration. Here we have shown that postnatal ablation of RPE mitochondrial oxidative phosphorylation in mice triggers gradual epithelium dedifferentiation, typified by reduction of RPE-characteristic proteins and cellular hypertrophy. The electrical response of the retina to light decreased and photoreceptors eventually degenerated. Abnormal RPE cell behavior was associated with increased glycolysis and activation of, and dependence upon, the hepatocyte growth factor/met proto-oncogene pathway. RPE dedifferentiation and hypertrophy arose through stimulation of the AKT/mammalian target of rapamycin (AKT/mTOR) pathway. Administration of an oxidant to wild-type mice also caused RPE dedifferentiation and mTOR activation. Importantly, treatment with the mTOR inhibitor rapamycin blunted key aspects of dedifferentiation and preserved photoreceptor function for both insults. These results reveal an in vivo response of the mature RPE to diverse stressors that prolongs RPE cell survival at the expense of epithelial attributes and photoreceptor function. Our findings provide a rationale for mTOR pathway inhibition as a therapeutic strategy for retinal degenerative diseases involving RPE stress.

Authors

Chen Zhao, Douglas Yasumura, Xiyan Li, Michael Matthes, Marcia Lloyd, Gregory Nielsen, Kelly Ahern, Michael Snyder, Dean Bok, Joshua L. Dunaief, Matthew M. LaVail, Douglas Vollrath

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Figure 5

Activation of the HGF/c-Met pathway in RPEΔMT mice is critical for RPE cell survival.

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Activation of the HGF/c-Met pathway in RPEΔMT mice is critical for RPE c...
(A) Immunoblot detects increased HGF and phosphorylated c-Met (Y1234/1235) in RPE cells from pigmented RPEΔMT mice at 14 weeks, compared with that in control. (B–E) Original magnification, ×400. Immunostaining of retinal sections shows increased reactivity of HGF (C) and p-c-Met (Y1234/1235) (E) in 22-week-old albino RPEΔMT mice. (F) Immuno­blot shows diminished p-c-Met (Y1234/1235) reactivity in 26-week-old albino RPEΔMT mice at 2 days PI of PHA-665752, a selective c-Met inhibitor. (G) Quantification of total remaining RPE cells at 2 days PI (normalized by the number of cells in vehicle-injected Tfamloxp/loxp control mice) reveals a significant loss of RPE cells in RPEΔMT mice treated with PHA-665752 (PHA) (n = 3) versus RPEΔMT mice treated with vehicle (Veh) (n = 3). §P < 0.01. (H and I) Immunostaining detects activated caspase-9–reactive RPE cells (green) in PHA-665752–injected RPEΔMT mice (I, arrows; inset is higher magnification image from another area). (J and K) Staining for phalloidin and cre on RPE flat mounts. (K) Z-scanning images (20-μm stack) show large areas of atrophic RPE with attenuated phalloidin staining and few, condensed cre-expressing RPE cells (arrows) in PHA-665752–treated RPEΔMT mice. (J) No effect is observed in vehicle-treated RPEΔMT mice. (H–K) Original magnification, ×200. (L and M) Light microscopy shows a denuded Bruch’s membrane and tiny pyknotic RPE cells (arrows) in PHA-665752–treated RPEΔMT mice (M), whereas RPE remains thickened and intact in vehicle-treated RPEΔMT mice (L). Dotted red lines in L and M denote the approximate edge of the outer segment layer. Original magnification, ×630.

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