Researchers have identified a pathway which offers new targets for potentially preventing and treating diabetic eye disease using a combination of antioxidants and an inhibitor.
High blood glucose levels can end up killing certain cells in the eyes and kidneys in diabetes patients, which is why diabetes is the leading cause of adult blindness and of kidney failure. One main route for this destruction is due to high glucose producing oxidative stress through the NF-kB molecular pathway, but success has been elusive for drugs targeting that pathway.
“Previously it was thought that oxidants are the major pathway, but antioxidants don’t seem to work in clinical trials,” notes senior author George L. King.
The researchers have now clarified the complications issue by detecting a second, independent pathway, which offers new targets for preventing and treating diabetic eye disease.
“That clinical observation made it clear that we don’t know all the mechanisms involved,” says lead author Pedro Geraldes. Expanding the search for what goes wrong as glucose levels climb, the researchers studied the effects on retinal pericytes (supportive tissue cells found near small blood vessels).
Scientists had long known that the protein PDGF, a growth factor, is essential to a cell-survival pathway that is required to keep these retinal cells alive. Working both in cultured cells and diabetic animals, Geraldes traced a molecular cascade that ends up increasing the expression of the protein SHP-1, which de-activates PDGF activity and thus triggers cell death.
“What’s exciting is that we finally have an explanation for why antioxidant drugs may not work, because there’s a parallel pathway,” says King. “We’ll need an inhibitor of SHP-1 together with antioxidants to have a realistic chance of preventing or stopping diabetic eye disease.”
“We think this is also applicable to diabetic kidney disease, because we observed a similar increase in SHP-1 in the kidneys of diabetic animals,” King adds. Additionally, understanding the role that SHP-1 plays in cell survival pathways may shed light on studies of cancer and other diseases, he says.
The researchers will test the mechanism in human cells and work on potential therapies based on targeting SHP-1.
References:
1. Pedro Geraldes, et al. Activation of PKC-? and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nature Medicine. doi:10.1038/nm.2052.
