Study shows why thiazolidinediones cause edema and helps understand role of kidneys in hypertension

In related discoveries with far-reaching implications for treating diabetes and understanding hypertension, University of Utah researchers have learned why thiazolidinediones (TZDs), a major anti-diabetes drug, cause edema and also have found a new pathway critical to fluid metabolism. Identification of this pathway may help understand fundamental mechanisms of blood pressure control.

Using knockout-gene technology, the University of Utah-School of Medicine researchers found that when TZD is activating a nuclear receptor, the peroxisome proliferator-activated receptor gamma, in the collecting duct in the kidney, it serves as a mechanism for fluid retention, or edema. The researchers suggest that the distal nephron, for example the collecting duct, is crucial for regulation of sodium balance and blood pressure. The research is published this week in the Proceedings of the National Academy of Sciences online.

The discoveries may point the way to developing different drugs to treat Type II diabetes and open an entirely new area in the study of hypertension, according to Tianxin Yang, M.D., Ph.D., the two-year study's principal investigator, associate professor of internal medicine at the U medical school, and staff physician at the George E. Wahler Veterans Affairs Medical Center in Salt Lake City.

An estimated 18 million Americans suffer from diabetes. TZD compounds have been shown to be highly effective in lowering blood glucose and lipid levels and in controlling blood pressure.

"It's almost a perfect drug for diabetes," Yang said.

But many diabetics who use TZD eventually have to discontinue the drug because it causes edema. About 1 percent of people who take TZD get pulmonary edema and chronic heart failure, both being potentially life-threatening conditions.

TZD works by activating PPAR-gamma, a receptor that helps sensitize the body to insulin. PPAR is found in muscle, fat, kidney, and heart and controls fatty acid and lipid metabolism. In the kidney, PPAR is found in the collecting duct, a critical site for the control of fluid metabolism.

To test the role of PPAR in edema, Yang created mice that specifically lacked PPAR-gamma in the collecting duct. He then administered TZD to these mice, as well as to a control group that didn't lack PPAR-gamma.

The mice not lacking PPAR-gamma showed about a 10 percent average increase in body weight because of fluid retention. The blood plasma volume of these mice increased by one-third, Yang said. But the mice bred without PPAR-gamma experienced no increase in body weight in response to the drug, according to Yang.

"This tells us that the body weight gain is regulated by PPAR-gamma in the collecting duct," he said. "We also found this drug decreased the sodium excretion in urine, so this could explain the fluid retention."

The mice without PPAR in the collecting ducts incurred no changes in sodium reabsorption, while those with PPAR excreted less sodium through urination. Yang said that the distal nephron, which is usually subject to hormone regulation in the kidney, serves as a key pathway for keeping an accurate amount of sodium in the body.

Hypertension affects one in four U.S. adults and long had been considered a cardiovascular disease. But research now also focuses on the kidneys and the role of the distal nephron in retaining sodium opens a new area for study, he said.