Pharmaceutical Induction of PGC-1α Promotes Retinal Pigment Epithelial Cell Metabolism and Protects against Oxidative Damage.
Sangeeta SatishHannah PhiliposeMariana Aparecida Brunini RosalesMagali Saint-GeniezPublished in: Oxidative medicine and cellular longevity (2018)
Retinal pigment epithelium (RPE) dysfunction due to accumulation of reactive oxygen species and oxidative damage is a key event in the development of age-related macular degeneration (AMD). Here, we examine the therapeutic potential of ZLN005, a selective PGC-1α transcriptional regulator, in protecting RPE from cytotoxic oxidative damage. Gene expression analysis on ARPE-19 cells treated with ZLN005 shows robust upregulation of PGC-1α and its associated transcription factors, antioxidant enzymes, and mitochondrial genes. Energetic profiling shows that ZLN005 treatment enhances RPE mitochondrial function by increasing basal and maximal respiration rates, and spare respiratory capacity. In addition, ZLN005 robustly protects ARPE-19 cells from cell death caused by H2O2, ox-LDL, and NaIO3 without exhibiting any cytotoxicity under basal conditions. ZLN005 protection against H2O2-mediated cell death was lost in PGC-1α-silenced cells. Our data indicates that ZLN005 efficiently protects RPE cells from oxidative damage through selective induction of PGC-1α and its target antioxidant enzymes. ZLN005 may serve as a novel therapeutic agent for retinal diseases associated with RPE dystrophies.
Keyphrases
- cell death
- cell cycle arrest
- skeletal muscle
- oxidative stress
- induced apoptosis
- transcription factor
- age related macular degeneration
- genome wide identification
- genome wide
- gene expression
- signaling pathway
- anti inflammatory
- cell proliferation
- dna methylation
- copy number
- deep learning
- smoking cessation
- high intensity
- replacement therapy
- dna binding
- low density lipoprotein