Nuevo objetivo de tratamiento para la retinopatía diabética

Scientists have identified a new target for reducing dysfunctional blood vessel development in the eyes of people with diabetic retinopathy.

In oxygen-compromising conditions like diabetes, the body grows new blood vessels to help, but the result is often leaky, dysfunctional vessels that make bad matters worse.

Now scientists have identified a new target for reducing that dysfunctional blood vessel development in the eye in a common condition called diabetic retinopathy, the leading cause of blindness in working-age adults.

“If we block the adenosine receptor A2a, the blood vessels will not leak and not as many new blood vessels will grow,” dice el Dr.. Yuqing Huo, chief of the Vascular Inflammation Program at the Vascular Biology Center at the Medical College of Georgia at Augusta University.

Un inhibidor de la A2a receptor de adenosina ya está en ensayos clínicos para la enfermedad de Parkinson,,en,La adenosina es un componente estructural natural de esenciales para el cuerpo básicas como ADN y ARN, así como el omnipresente ATP combustible celular,,en,Puede ayudar a los vasos sanguíneos se expanden,,en,batalla ritmos cardíacos e incluso mala proporcionar alivio del dolor,,en,Su familia de receptores incluye A2a receptor de adenosina,,en,que es importante para la retina y que se encuentra en las células endoteliales que revisten los vasos sanguíneos,,en,dice Huo,,zh-CN,autor del estudio co-correspondiente en la revista Nature Communications,,en,Cuando los niveles de oxígeno son buenos,,en,su expresión es baja en las células endoteliales,,en,Pero en la diabetes,,en,donde los niveles de oxígeno bajan,,en,la expresión del receptor de adenosina A2a va hacia arriba y nace un círculo vicioso,,en.

Adenosine is a natural structural component of basic body essentials like DNA and RNA as well as the ubiquitous cell fuel ATP. It can help blood vessels expand, battle bad heart rhythms and even provide pain relief. Its family of receptors includes adenosine receptor A2a, which is important for the retina and found on the endothelial cells that line blood vessels, says Huo, co-corresponding author of the study in the journal Nature Communications.

When oxygen levels are good, their expression is low in endothelial cells. But in diabetes, where oxygen levels go down, adenosine A2a receptor expression goes way up and a vicious cycle is born.

Endothelial cells that line the blood vessels of the retina begin to shrink, even disappear in diabetes. Expression of adenosine receptor A2a increases, apparently to enable endothelial cells to take up more glucose that can be converted to energy to help restore good oxygen and blood flow. En este caso, that means repairing existing blood vessels and growing new ones in a process called angiogenesis. But in a scenario where the cells don’t use energy efficiently or build blood vessels well it’s actually called “pathological angiogenesis.” Old and new blood vessels alike readily bleed or contract, leading to hemorrhage and/or retinal detachment and blindness, the scientists write.

Drs. Zhiping Liu  and Yuqing Huo
DRS. Zhiping Liu (izquierda) and Yuqing Huo

“They grow too much, too fast,” Huo says. It’s not yet clear whether it’s the high glucose levels of diabetes and/or the resulting inflammation or other factors that increase expression of adenosine receptor A2a. Huo notes that adenosine’s many actions include an anti-inflammatory effect.

But the work of Huo and his colleagues indicates that however it happens adenosine receptor A2a’s higher profile role in this scenario makes it a likely treatment target.

A key problem appears to be that the receptor aids the inefficiency of endothelial cells. These cells generate about 85 percent of their fuel through glycolysis, a way to convert glucose to the cell fuel ATP without using oxygen. Even with plenty of oxygen handy, endothelial cells appear to like this method. Por la comparación, cellular respiration, which requires oxygen, produces nearly 40 molecules of ATP per molecule of glucose versus only about two ATP molecules per glucose molecule with glycolysis.

When the scientists activate the receptor, it promotes the enzymes that promote glycolysis. Increased use of this inefficient energy production process of glycolysis has been shown to occur in endothelial cells in people with proliferative diabetic retinopathy.

Por el contrario, when the scientists knocked out or deleted adenosine receptor A2a from endothelial cells, it decreased glycolysis. Blocking glycolysis, a su vez, dramatically inhibited blood vessel proliferation and sprouting of endothelial cells that overexpress the receptor.

When oxygen levels were more normal, knocking out or deleting adenosine receptor A2a didn’t seem to have that much impact on glycolysis, possibly because the receptor’s expression is not that high when oxygen levels are normal, the scientists suspect.

All the reciprocal cause and effect they found supports the new idea that the receptor promotes glycolysis, which promotes pathological angiogenesis in retinopathies, Huo says.

Much work remains. Por ejemplo, they have not yet figured out the connection between the adenosine receptor A2a and VEGF receptors, but there has to be some synergy, Huo says, since as its name implies, factor de crecimiento endotelial vascular, or VEGF, also is clearly important to endothelial cell repair and new blood vessel formation.

In the right environment, adenosine A2a receptor has a positive role in blood vessel formation as well: activation of the receptor in a mouse model of wound healing shows increased activation of healthy angiogenesis that aids recovery.

His lab also wants to try in their animal models and human retinal tissue, the adenosine receptor A2a inhibitor showing success and safety in patients with Parkinson’s disease. In Parkinson’s, expression of adenosine receptor A2a goes up in a part of the brain involved with voluntary movement.

Inhibitors under study for that degenerative condition appear to decrease uncontrolled movement and generally slow disease progression without significant side effects, Huo says.

It’s the safety and effectiveness in that condition combined with his findings in the retina, that have Huo planning to use existing inhibitors in his studies. He’s also working with co-corresponding author and chemist, Dr.. Mei Hong, of the Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, to develop another adenosine receptor A2a inhibitor.

Endothelial cells likely opt to use glycolysis because during development, many are formed in a hypoxic, or no oxygen, environment, Huo notes. Many other cell types only turn to glycolysis when they are stressed. He adds that caffeine is a not-very-specific blocker of adenosine receptor A2a.

Casi 10 percent of Americans have diabetes, según la Asociación Americana de Diabetes. Hasta 45 percent of those individuals have some degree of diabetic retinopathy, según el Instituto Nacional del ojo.

The retina is inside the back of the eye, a multi-layered and vascular tissue, which receives light and transforms it to a neural impulse that goes to the brain. The optic nerve that transmits the neural impulses is in the center of the retina, and the retina’s major blood vessels radiate from the optic nerve.

In addition to efforts to better manage blood glucose and blood pressure levels, current therapies for diabetic retinopathy include laser surgery to attempt to seal leaky blood vessels as well as surgery to remove vitreous gel, blood and scar tissue to better enable light to again focus on the retina. Direct injections into the eye of steroids may help with swelling and an anti-VEGF treatment may help reduce growth of the leaky vessels.

Postdoctoral fellow Dr. Zhiping Liu is the study’s first author. Huo is a professor in the MCG Department of Cellular Biology and Anatomy.

La investigación fue apoyada por las subvenciones de los institutos nacionales de salud, Asociación Americana del corazón, the National Key Basic Research Program of China, the National Natural Science Foundation of China, Guangdong Natural Science Foundation, the Shenzhen Science and Technology Innovation Committee and the Shenzhen Peacock Program.
Likely new treatment target identified for diabetic retinopathy

Fuente: Colegio médico de Georgia en la Universidad de Augusta
Revista: Comunicaciones de naturaleza
Fuente de financiación: Institutos nacionales de salud, Asociación Americana del corazón, National Key Basic Research Program of China, Fundación Nacional de Ciencias naturales de China, Guangdong Natural Science Foundation, Shenzhen Science and Technology Innovation Committee

Pie de foto

In oxygen-compromising conditions like diabetes, the body grows new blood vessels to help, but the result is often leaky, dysfunctional vessels that make bad matters worse.

Crédito de la foto: Phil Jones, Senior Photographer, Augusta University

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