Molecular Pathway Helps Determine Age-Related Macular Degeneration Type

Age-related macular degeneration (AMD) is a disease that affects a person’s central vision. It can result in severe loss of central vision, but people rarely go blind from it. While all patients start with “dry” AMD, the condition can advance to severe dry AMD, or another kind of AMD known as “wet” AMD. Wet AMD is characterized by abnormal blood vessel growth in the eye, which leaks fluid and damages tissue. In advanced “dry” AMD (also called geographic atrophy), the retina thins out as cells die. Now, Wilmer Eye Institute researchers at Johns Hopkins Medicine report they have found how a molecular pathway contributes to what kind of AMD a patient could develop.

Their findings are published in Proceedings of the National Academy of Sciences in an article titled, “Pathologic vs. protective roles of hypoxia-inducible factor 1 in RPE and photoreceptors in wet vs. dry age-related macular degeneration.”

“It has previously been reported that antioxidant vitamins can help reduce the risk of vision loss associated with progression to advanced AMD, a leading cause of visual impairment among the elderly,” the researchers wrote. “Nonetheless, how oxidative stress contributes to the development of choroidal neovascularization (CNV) in some AMD patients and geographic atrophy (GA) in others is poorly understood. Here, we provide evidence demonstrating that oxidative stress cooperates with hypoxia to synergistically stimulate the accumulation of hypoxia-inducible factor (HIF)-1α in the retinal pigment epithelium (RPE), resulting in increased expression of the HIF-1-dependent angiogenic mediators that promote CNV.”

The Wilmer Eye Institute researchers focused 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 the protein HIF-1 have been previously implicated in the development of AMD.

The researchers observed 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.

They induced 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.

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.

“This may be why oxidative stress in older patients, who also have other predisposing factors to low oxygen in the retina, leads to the wet form of age-related macular degeneration,” explained study co-author Akrit Sodhi, MD, PhD, associate professor of ophthalmology and the Branna and Irving Sisenwein professor of ophthalmology at the Johns Hopkins University School of Medicine and Wilmer Eye Institute. 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, he explained.

While these experiments shed light on how wet AMD may form, they did not fully explain how oxidative stress could contribute to advanced dry AMD, caused by cell death. The researchers 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.

They removed HIF-1 in the cells, then induced 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.

“This is an early step towards understanding molecular mechanisms whereby HIF-1 contributes to both wet and dry AMD,” said Sodhi. “Our studies demonstrate how two cell populations react to oxidative stress: both alter HIF-1 levels, but in one cell this response can promote wet AMD and in the other it can protect against advanced dry AMD.”

“Wet and dry AMD may be different sides of the same coin—if tissues in the eye are pushed to protect you from one, you may end up getting the other,” added Sodhi. A more precise understanding of HIF-1’s role in the eye’s response to oxidative stress, he said, may help advance the search for better wet and dry AMD treatments.

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