Premium
Paradoxical effects of PGC‐1 isoforms on retinal pigment epithelium: Implication for neovascular retinal diseases
Author(s) -
SAINTGENIEZ MAGALI,
Charles Quincy,
Rosales Mariana,
Khadka Arogya,
Iacovelli Jared
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.976.11
Subject(s) - retinal pigment epithelium , mitochondrial biogenesis , oxidative phosphorylation , biology , microbiology and biotechnology , mitochondrion , population , oxidative stress , retinal , endocrinology , biochemistry , medicine , environmental health
Age‐related macular degeneration (AMD) is the leading cause of blindness in the elderly population of industrialized countries. A compelling set of evidences indicates that oxidative damage and mitochondrial dysfunctions of the retinal pigment epithelium (RPE) are key early events in age‐related macular degeneration (AMD) but the root mechanisms for RPE pro‐angiogenic switch remain unclear. The transcriptional co‐activators, peroxisome proliferator‐activated receptor‐gamma coactivator‐1alpha and beta (PGC‐1α and β) are critical regulators of mitochondrial biogenesis and oxidative metabolism in many tissues. We recently demonstrated that RPE maturation in vitro is correlated with PGC‐1α induction, mitochondrial biogenesis and increased oxidative phosphorylation. Furthermore, we showed that PGC‐1α controls RPE cells oxidative metabolism and efficiently protects cells from cytotoxic oxidative damage. Remarkably, our results indicate that, conversely to PGC‐1α, PGC‐1β expression is repressed during RPE maturation in a PGC‐1α‐dependent manner. Here we examined the role of PGC‐1β in RPE biology and response to oxidative damage. We showed that while forced expression of PGC‐1β stimulates RPE mitochondrial respiration similarly to PGC‐1α, PGC‐1β significantly repressed the expression of critical antioxidant transcription factors (FOXO3 and NFE2L2) and enzymes (HMOX1, CAT) leading to increased oxidative damage and cell death in RPE exposed to cytotoxic levels of H 2 O 2 (0.5 mM for 18 hours). We next evaluated whether AMD‐related toxicants could induce PGC‐1β expression in cultured RPE and demonstrated that PGC‐1β, but not PGC‐1α, is selectively induced by cytotoxic doses of oxidized LDL (500 μg/ml for 24 hrs) while non‐oxidized LDL had no effect. Finally we demonstrated that PGC‐1β overexpression in RPE robustly induced PlGF (Placenta Growth factor) expression but not VEGFA and strongly repressed the RPE‐secreted anti‐angiogenic factors, thrombospondin‐1 ( THBS1 ) and PEDF . All together, these findings indicate that PGC‐1s exert paradoxical functions in RPE and that pathologic induction of PGC‐1β may promote RPE oxidative damage and choroidal neovascularization. Support or Funding Information Supported by the National Institutes of Health (1R01EY023682 to M.S.G.), a Research to Prevent Blindness Unrestricted Grant (M.S.G), donations to the Macular Degeneration Research, a program of the BrightFocus Foundation (M.S.G) and the NIH National Eye Institute core grant P30EY003790.