Department of Ophthalmology & Visual Sciences
Vanderbilt University Medical Center
Nashville, Tennessee

BASIC RESEARCH PROJECT
The Cellular Mechanisms by which Arginine and Citrulline promote vision threatening Diabetic Retinopathy

Research Interests
Diabetic retinopathy (DR) is a leading cause of blindness throughout the world. DR is challenging to treat, and it is critical that new treatments be developed that can slow DR progression and reduce the chance of severe vision loss. Dr. Brantley’s lab recently discovered that blood levels of two molecules, arginine and citrulline, are elevated in patients with DR. To investigate this, the research team added arginine and citrulline together to retinal endothelial cells, the cells that make up the blood vessels in the retina. They found that arginine and citrulline caused the endothelial cells to become leaky and to form new blood vessel tubes, two classic features of DR. With continued support from Retina Research Foundation, Dr. Brantley is now working to determine exactly how these molecules promote diabetic retinopathy.

Plans for 2021
The purpose of this study is to understand precisely how arginine and citrulline alter the cells in the retina that are specifically involved in DR. Dr. Brantley’s research team will determine exactly how arginine and citrulline function in retinal endothelial cells to cause retinopathy as well as how they may be able to modify current treatments for DR.  Dr. Brantley believes these studies will help to develop new ways of treating, or even preventing, diabetic retinopathy.

In 2021, Dr. Brantley will finalize the cellular pathway studies with specific inhibitors of arginase and nitric oxide synthase to confirm that arginine and citrulline induce angiogenesis through the nitric oxide pathway.

Specific Aims: Aim 1. Confirm the cellular pathway by which arginine and citrulline induce angiogenesis in retinal endothelial cells. Aim 2. Determine the changes in membrane protein structure by which arginine and citrulline increase vascular permeability in retinal endothelial cells. Aim 3. Determine if the angiogenesis-promoting effects of arginine and citrulline are independent of VEGF in retinal endothelial cells.

Progress in 2020
The data thus far suggest that treatment of retinal endothelial cells with arginine and citrulline leads to increase nitric oxide synthase activity and nitric oxide production.  Arginine and citrulline in combination also reduce arginase activity.  These data support the hypothesis that arginine and citrulline induce new blood vessel growth through the nitric oxide pathway.