image: This shows Dr. Ruth Caldwell, cell biologist in the Vascular Biology Center at the Medical College of Georgia at Georgia Regents University, Department Chair of Pharmacology and Toxicology at Medical College of Georgia at Georgia Regents University. view more
Credit: Phil Jones
AUGUSTA, Ga. – Scientists want to shore up a good relationship that goes bad in diabetes.
Things are good when foods such as poultry and fish ensure ample supplies of the amino acid L-arginine are around to team with the enzyme arginase and help the liver eliminate ammonia, a potentially lethal byproduct of the body's constant use of proteins.
Diabetes alters the dynamic, causing inflammation that produces too much arginase inside the cells lining blood vessels in the retina. The excess arginase starts scarfing up L-arginine, also needed to make nitric oxide, a powerful and short-lived signaling molecule that enables blood vessels to relax. So blood pressure inside the eye – and throughout the body – goes up.
Damage multiplies as the enzyme that normally produces nitric oxide instead starts making superoxide, or free radicals, which, in excess, damage pretty much everything. Superoxide turns around and confiscates what little nitric oxide is available to make even more free radicals, said Dr. Ruth Caldwell, cell biologist in the Vascular Biology Center at the Medical College of Georgia at Georgia Regents University, describing how one soured relationship yields many others.
While high glucose is the real instigator, stabilizing levels of arginase and its related players is likely a more realistic option for protecting the sight – and maybe more – of patients struggling to maintain healthy blood sugar levels.
Caldwell has teamed with colleague and husband, Dr. William Caldwell, who studies the regulation of blood flow, on a new $2.2 million grant from the National Eye Institute to optimize the process.
"It's a positive feedback which is negative in its effect on the body," said William Caldwell, Chairman of the MCG Department of Pharmacology and Toxicology. "Eventually you start losing blood vessels inside the retina. When you do, the retina tries to make more blood vessels and they leak and grow in the wrong place and get in the way of the light signal."
To restore a healthy relationship, the Caldwells want to level out arginase activity, using arginase inhibitors, which are already used for some acute problems, such as parasitic infections, but not chronically as will be necessary in diabetes.
"We have given the arginase inhibitors to animals and they get better," William Caldwell said. "Their blood pressure goes down, they have better blood flow, and we can't see any toxic effects."
They also want to marginally reduce the activity of other key steps in the process, including the production of free radicals and signaling events that lead to high levels of arginase and downstream disasters.
"Normalization is what we are trying to achieve," said Ruth Caldwell. "There is a chain of events between reactive oxygen species and arginase going up. We are looking at those steps to see if we can take a little piece of them all."
Their new studies are in animal models of type 1 and 2 diabetes as well as the liquid portion of the eye and donor eyeballs from patients with and without diabetes.
The scientists note the additional irony that elevated arginase levels in response to high glucose and free radicals likely is a reparative attempt, because their pairing also increases cell proliferation and the laying down of collagen, which are important for repair but go too far in diabetes.
"Arginase comes up like it is supposed to but does not go back down to allow the repair to be complete," Ruth Caldwell said. Blood vessels that can't properly relax start getting clogged with cells. Additionally, neurotoxins build up in the eye causing retinal cell death and more damage.
It's likely their interventions will benefit more than the eye. "Our initial focus was the heart and we showed that there's coronary vascular dysfunction and fibrosis in the heart, which is related to arginase," William Caldwell said.
In her animal models, Ruth Caldwell finds high levels of arginase in the retina before there is any obvious sign of damage so higher levels may also predict risk for the eye and possibly elsewhere. They already know that arginase levels in the blood are a good indicator of levels in other tissues so keeping an eye on arginase levels is doable.