Oxidant Activated Nuclear Receptors in AMD Pathogenesis

Progress Updates

Early dry age-related macular degeneration (AMD) is characterized by the accumulation of lipid- and protein-rich deposits called drusen below the retinal pigment epithelium (RPE). Though the mechanisms underlying the pathogenesis of drusen formation are still under investigation, oxidant injury of RPE cells is believed to play an important role in progression and potentially initiation of the disease. Dr. Malek’s team has recently observed that the activity of the aryl hydrocarbon receptor (AhR; a DNA-binding protein which is activated in response to toxins) is increased in RPE cells following exposure to various oxidants, such as those found in cigarette smoke. Acute AhR activation results in an increase in levels of enzymes involved in toxin clearance while chronic AhR activation has been shown to increase oxidative stress and production of reactive oxygen species (ROS) in the mitochondria (the energy powerhouses of the cell). Therefore, the team hypothesized that acute activation of the receptor is a necessary mechanism involved in RPE cell health while chronic activation of the receptor is not ideal since it results in mitochondrial dysfunction and production of ROS, mechanisms involved in AMD. Overall disruptions to the AhR pathway in turn leads to RPE injury, increased susceptibility to oxidative damage, extracellular matrix (structural) dysfunction and stimulation of deposits under the RPE—key features of dry AMD.

During the past year, the team has demonstrated that AhR activation with native and pharmacological ligands (i.e. protein and drug activators) results in mitochondrial dysfunction—specifically, a decrease in mitochondrial membrane potential, an increase in ROS production, and structural changes observed at high magnification. Furthermore the team has completed analysis of aged wild type and AhR knockout mice in the presence or absence of oxidant injury. They observed that AhR knockout mice present with several features of human AMD, including impaired visual function, and accumulation of sub-RPE deposits, which is further exacerbated in mice exposed to oxidant injury. These findings demonstrate the potential involvement of a novel signaling pathway in the pathogenesis of AMD, and these mice may serve as an animal model to study deposit formation and test out potential therapeutics for removal or prevention of deposits with age.