AHSC Research Matters: Unexpected Discovery Leads to Insight for Dry Eye Disease

April 8, 2015

Researchers at the Arizona Health Sciences Center have discovered a potential cause of dry eye disease—a disease that afflicts millions of people in the United States.

Researchers at the UA Steele Children’s Research Center made an unexpected discovery into the role of NHE8, a sodium/hydrogen exchanger protein.

The research was led by UA Steele Center Director Fayez K. Ghishan, MD, professor and head, Department of Pediatrics, and Steele Center researcher Hua Xu, PhD, associate professor, UA Department of Pediatrics. They collaborated with Mingwu Wang, MD, PhD, associate professor, UA Department of Ophthalmology and Vision Science.

NHEs are a group of membrane proteins that function to exchange extracellular sodium (Na+) for intracellular hydrogen (H+). NHE proteins contribute to many physiological functions, such as intracellular (within cells) acidic (pH) regulation, cell volume regulation and sodium absorption. They play an important role by transporting sodium and electrolytes through the gastrointestinal tract.

In previous research, Drs. Ghishan and Xu discovered that NHE8 plays a role in mucosal protection in the intestinal tract and in male reproduction. “When we deleted NHE8 in mice, we observed that they developed gastric ulcerations, became more susceptible to infections and the male mice became sterile,” said Dr. Ghishan.
“And now, we have discovered that mice lacking NHE8 expression also develop dry eye disease,” he said.
“We observed that NHE8 protein is highly expressed in the ocular surface epithelial cells and the lacrimal glands in humans and mice,” said Dr. Xu. “Loss of NHE8 function in mice resulted in decreased tear production and mucous secretion and increased corneal staining and elevated inflammatory cytokine expression in the ocular surface, and hence possibly led to dry eye symptoms.”

Dry eye disease (DED) is a very common eye disease, especially in Arizona, due to low humidity and high temperatures. Individuals with DED have symptoms of discomfort, visual disturbance and even loss of vision. The disease affects millions of people, and billions of dollars are spent annually for treatment in the United States alone.

Drs. Ghishan and Xu collaborated with Dr. Wang, who is an expert in treating patients with dry eye disease. Dr. Wang helped characterize dry eye phenotypes in NHE8-deficient mice. “It was very interesting to observe clinical dry eye characteristics in the NHE8-deficient mice in comparison to the wild type mice,” said Dr. Wang. “Much more research needs to be done to delineate the exact underlying mechanism,” he added. 

“The causes for DED are very complex,” said Dr. Xu. “We believe this new discovery will lead us to a better understanding of the causes of dry eye disease, and we hope this finding will provide insight for new treatment strategies for this very common disease.”

Their study, “Loss of NHE8 expression impairs ocular surface function in mice,” was published in the American Journal of Physiology—Cell Physiology, in January.

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-073638 (F. K. Ghishan and H. Xu), Research to Prevent Blindness Foundation (M. Wang), and University of Arizona Faculty Research Seed Grant (M. Wang).