Dataset Information

?v?5 Integrin/FAK/PGC-1? Pathway Confers Protective Effects on Retinal Pigment Epithelium.

ABSTRACT:

Purpose

To elucidate the mechanism of the induction of peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?) by photoreceptor outer segments (POS) and its effects on retinal pigment epithelium (RPE).

Methods

PGC-1? upregulation by POS was confirmed in ARPE-19 cells and in RPE ex vivo. To elucidate the mechanism, siRNAs against ?5 integrin, CD36, Mer tyrosine kinase (MerTK), and Atg5, blocking antibodies against CD36 and MerTK, and a specific inhibitor for focal adhesion kinase (FAK) were used. We examined the effect of POS-induced PGC-1? upregulation on the levels of reactive oxygen species (ROS), mitochondrial biogenesis, senescence-associated ?-galactosidase (SA-?-gal) after H2O2 treatment, and lysosomal activity. Lysosomal activity was evaluated through transcriptional factor EB and its target genes, and the activity of cathepsin D. Lipid metabolism after POS treatment was assessed using Oil Red O and BODIPY C11. RPE phenotypes of PGC-1?-deficient mice were examined.

Results

POS-induced PGC-1? upregulation was suppressed by siRNA against ?5 integrin and a FAK inhibitor. siRNAs and blocking antibodies against CD36 and MerTK enhanced the effect of POS on PGC-1?. The upregulation of PGC-1? increased the levels of mRNA for antioxidant enzymes and stimulated mitochondrial biogenesis, decreased ROS levels, and reduced SA-?-gal staining in H2O2-treated ARPE-19 cells. PGC-1? was critical for lysosomal activity and lipid metabolism after POS treatment. PGC-1?-deficient mice demonstrated an accumulation of type 2 lysosomes in RPE, thickening of Bruch's membrane, and poor choriocapillaris vasculature.

Conclusions

The binding, but not the internalization of POS confers protective effects on RPE cells through the ?v?5 integrin/FAK/PGC-1? pathway.

SUBMITTER: Roggia MF

PROVIDER: S-EPMC4526642 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

αvβ5 Integrin/FAK/PGC-1α Pathway Confers Protective Effects on Retinal Pigment Epithelium.

Roggia Murilo F MF Ueta Takashi T

PloS one 20150805 8

<h4>Purpose</h4>To elucidate the mechanism of the induction of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) by photoreceptor outer segments (POS) and its effects on retinal pigment epithelium (RPE).<h4>Methods</h4>PGC-1α upregulation by POS was confirmed in ARPE-19 cells and in RPE ex vivo. To elucidate the mechanism, siRNAs against β5 integrin, CD36, Mer tyrosine kinase (MerTK), and Atg5, blocking antibodies against CD36 and MerTK, and a specific inhibitor for focal adhe ...[more]

PMID: 26244551

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