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

J Clin Invest. 2011 Jan;121(1):369-83. doi: 10.1172/JCI44303. Epub 2010 Dec 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Cell Death
  • Cell Dedifferentiation / drug effects
  • Cell Dedifferentiation / physiology
  • Cell Movement
  • Cell Survival
  • Female
  • Glycolysis
  • Hepatocyte Growth Factor / metabolism
  • Hypertrophy
  • Male
  • Mice
  • Mice, Transgenic
  • Oxidative Phosphorylation
  • Photoreceptor Cells, Vertebrate / drug effects
  • Photoreceptor Cells, Vertebrate / metabolism
  • Photoreceptor Cells, Vertebrate / pathology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-met / metabolism
  • Retinal Degeneration / etiology*
  • Retinal Degeneration / metabolism
  • Retinal Degeneration / pathology
  • Retinal Degeneration / prevention & control
  • Retinal Pigment Epithelium / drug effects
  • Retinal Pigment Epithelium / metabolism*
  • Retinal Pigment Epithelium / pathology*
  • Signal Transduction
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • HGF protein, mouse
  • Hepatocyte Growth Factor
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-met
  • Proto-Oncogene Proteins c-akt
  • Sirolimus