Age- and/or disease-dependent imbalance between oxidants and antioxidant capacity has been proposed as an important contributor to the progressive dysfunction and atrophy of RPE during AMD. Exposure to environmental oxidants such as cigarette smoke
56 combined with the lifelong accumulation of pro-oxidative degradation products from OS phagocytosis
57 can lead to deleterious ROS levels and increased mitochondrial DNA damage. Susceptibility of RPE to oxidative stress is further enhanced by the dysregulation and/or decreased activity of key components of the cell's antioxidant mechanism observed during aging and/or AMD.
8,58 For example, CAT protein levels and activity were both found to be decreased in the aging eye.
9,59,60 Additionally, aged RPE failed to increase the expression of the transcription factor NFE2L2, a critical regulator of antioxidant enzymes, in response to oxidative insult, whereas such induction was observed in the RPE of younger animals.
61 We show here that overexpression of PGC-1α in RPE is able to powerfully increase the expression of multiple antioxidant enzymes including CAT, GPX1, PRDXs, and SOD2. Moreover, PGC-1α effectively reduced RPE cell death induced by H
2O
2 and hydroquinone, two potent oxidants that have been implicated in AMD pathogenesis.
62,63 CAT and GPX1 have been previously shown to protect RPE from H
2O
2-mediated damage and cell death,
64,65 and therefore, may be contributing to the cytoprotective effect of PGC-1α. Retinal pigment epithelium dysfunction and progressive atrophy of the outer retina induced by genetic deletion of
Sod1 or
Sod2 in mice suggest also a role for impaired superoxide clearance in AMD.
10,66 Recently, the
ARMS/HTRA1 AMD-associated risk haplotype has been associated with an altered SOD2 stress response in patient-derived iPS-RPE,
67 suggesting that RPE in patients carrying the
ARMS/HTRA1 risk alleles have increased susceptibility to oxidative damage and that gene therapy approaches to increase
SOD2 expression could serve as potential treatment for AMD. Surprisingly, overexpression of SOD2 alone in ARPE-19 increases protein oxidative damage likely due to cytoplasmic H
2O
2 accumulation.
65 However, when GPX1 was also overexpressed, protein carbonyls were reduced.
65 Therefore, the ability of PGC-1α to simultaneously induce the expression of both cytoplasmic and mitochondrial antioxidant enzymes in RPE would most likely counteract the effect of increased protein carbonyls secondary to SOD2 overexpression alone. This observation underscores the potential benefit of targeting PGC-1α to activate multiple and properly coordinated antioxidant responses.