Researchers of the University of Utah have found why thiazolidinediones (TZDs, glitazones ), a class of anti-diabetes drugs, cause edema.

Using knockout-gene technology, researchers found that when glitazone 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 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, the two-year study's principal investigator.

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.

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

Glitazone 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 glitazone 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.

Source: University of Utah Health Sciences Center, 2005


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