Abstract
Hypoxia affects the development and/or progression of several retinopathies. Decidual protein induced by progesterone (DEPP) has been identified as a hypoxia-responsive gene that may be part of cellular pathways such as autophagy and connected to retinal diseases. To increase our understanding of DEPP regulation in the eye, we defined its expression pattern in mouse and human retina and retinal pigment epithelium (RPE). Interestingly, DEPP expression was increased in an age-dependent way in the central human RPE. We showed that DEPP was regulated by hypoxia in the mouse retina and eyecup and that this regulation was controlled by hypoxia-inducible transcription factors 1 and 2 (HIF1 and HIF2). Furthermore, we identified three hypoxia response elements (HREs) about 3.5 kb proximal to the transcriptional start site that were responsible for hypoxic induction of DEPP in a human RPE cell line. Comparative genomics analysis suggested that one of the three HREs resides in a highly conserved genomic region. Collectively, we defined the molecular elements controlling hypoxic induction of DEPP in an RPE cell line, and provided evidence for an enrichment of DEPP in the aged RPE of human donors. This makes DEPP an interesting gene to study with respect to aging and age-related retinal pathologies.
Highlights
Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment and blindness among the elderly [1,2] and its prevalence is predicted to further increase with the aging of the human population [1,3]
decidual protein induced by progesterone (Depp) was upregulated in both mouse tissues that were exposed to acute hypoxia (Figure 1a, left panel)
To establish an in vitro model for the investigation of Depp regulation by hypoxia, we determined its expression in human primary retinal pigment epithelium (RPE) cells human retinal pigment epithelial cells (HRPEpiC) and in a human RPE cell line (ARPE-19) (Figure 1b)
Summary
Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment and blindness among the elderly [1,2] and its prevalence is predicted to further increase with the aging of the human population [1,3]. HIF transcription factors are composed of an oxygen-regulated HIFA and a constitutively expressed HIFB subunit. Prominent examples are genes involved in erythropoiesis and angiogenesis, such as erythropoietin (EPO) and vascular endothelial growth factor (VEGF) (reviewed in [21]), which are upregulated in an effort to improve tissue oxygenation. In an attempt to better understand the impact of hypoxia on the eye, we screened retinas of wild type mice exposed to acute hypoxia for differentially-regulated transcripts by genome microarrays and identified the decidual protein induced by progesterone (Depp) as being 35-fold upregulated in these conditions [27]. Using a luciferase reporter system, we identified three HREs that are responsible for the regulation of DEPP in hypoxic conditions. We performed a comparative analysis of the identified HREs to investigate the conservation across species
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