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Scientists Uncover Molecular Link Between Wet and Dry Macular Degeneration

(c) AAO

Wilmer Eye Institute researchers at Johns Hopkins Medicine have found how a molecular pathway — involving oxidative stress, or an imbalance of molecular oxygen in cells, and the protein HIF-1 — contributes to what kind of age-related macular degeneration (AMD) a patient could develop.

Researchers started by focusing on oxidative stress, which can increase in the body through common factors such as aging, exposure to cigarette smoke and high-fat/high-sugar diets. Both oxidative stress and HIF-1 have been previously implicated in the development of AMD.

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Specifically, investigators looked at changes in HIF-1 levels caused by oxidative stress in two eye cell populations: retinal pigment epithelium, which protects the retina and filters light, and retinal photoreceptors, nerve cells that convert light to brain signals.

Researchers began by inducing oxidative stress in retinal pigment epithelium cell lines, adding chemicals that created an imbalance of oxygen molecules. In response, the cells overproduced HIF-1 and another protein called VEGF, promoting blood vessel growth in the retina and mimicking wet AMD.

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Researchers conducted these same tests on cells in low-oxygen environments, as low oxygen is known to contribute to blood vessel overgrowth in wet AMD. HIF-1 and VEGF increased at even higher rates and concentrations.

Blood vessel growth is likely the eye’s attempt to increase oxygen flow when it’s starved for the molecule, but in wet AMD the eye overcompensates leading to vision loss.

While these experiments shed light on how wet AMD may form, they did little to explain how oxidative stress could contribute to advanced dry AMD, caused by cell death. In fact, researchers noticed that retinal pigment epithelium cells in the tissue they tested were resistant to cell death from oxidative stress. They turned to different cells, retinal photoreceptors, to understand dry AMD’s origins and the role of oxidative stress in disease development.

When the researchers induced oxidative stress in human and rodent photoreceptors, they saw an increase in HIF-1 production, similar to their previous experiments. However, they observed that photoreceptors were remarkably sensitive to oxidative stress, which caused cell death in the tissue, thus mimicking dry AMD.

The team investigated further by removing HIF-1 in the cells, then inducing oxidative stress. Cell death increased in HIF-1’s absence, demonstrating HIF-1’s protective role against the damaging effects of oxidative stress in photoreceptors and in dry AMD.

A more precise understanding of HIF-1’s role in the eye’s response to oxidative stress may help advance the search for better wet and dry AMD treatments.

Funding for this work was supported by the National Eye Institute, National Institutes of Health grants R01EY029750, R01EY025705, EY001765; the Research to Prevent Blindness, Inc., Special Scholar Award and unrestricted grant to Wilmer Eye Institute and University of Colorado; the Alcon Research Institute; the Steve J. Ryan Initiative for Macular Research; the Branna and Irving Sisenwein Professorship in Ophthalmology; the CellSight Development Fund; and the Doni Solich Family Chair in Ocular Stem Cell Research.


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