Sci. Aging Knowl. Environ., 22 June 2005
Vol. 2005, Issue 25, p. nf47
[DOI: 10.1126/sageke.2005.25.nf47]

NEWS FOCUS

Releasing the Pressure

Eliminating kidney protein in mice relieves swelling spurred by diabetes drugs

R. John Davenport

http://sageke.sciencemag.org/cgi/content/full/2005/25/nf47

Diabetes patients want to get a tighter grip on their metabolism without holding onto excess water, and new work might lead the way. Mice with a particular genetic alteration don't suffer from fluid accumulation, a dangerous side effect triggered by some antidiabetes drugs. The findings might help researchers fine-tune therapies.

In type 2 diabetes, cells respond reluctantly to the glucose-controlling hormone insulin, and blood sugar concentrations swing out of control. Drugs called thiazolidinediones (TZDs) restore fat and muscle cells' sensitivity to insulin by activating a protein called PPAR{gamma}. The drugs defuse some complications of diabetes, too. For instance, they stave off atherosclerosis by heightening PPAR{gamma}'s ability to quench inflammation. But TZDs aren't perfect. In many patients, fluid accumulates in tissues, causing weight gain and occasionally heart failure. No one knows why TZDs incite bloating, but the drugs might interfere with the kidneys' excretion of sodium or relax blood vessels, both of which can increase blood volume. The drugs might also cause blood vessels to spring leaks, letting fluid into tissues. Kidney cells produce PPAR{gamma}, so Tianxin Yang, a physiologist at the University of Utah in Salt Lake City, and colleagues investigated whether TZDs act on the protein there to cause fluid buildup.

The researchers engineered mice to lack PPAR{gamma} in their collecting ducts, kidney structures that reabsorb water and salt from waste fluid. Then they added a TZD to the rodents' food for 9 days; normal animals also ate the drug. Consistent with observations in people, normal animals on TZDs gained weight. In addition, their blood volume increased, a sign of fluid accumulation. Animals without PPAR{gamma} in their collecting ducts didn't gain weight, and their blood volume didn't increase as much as it did in normal mice.

Additional observations support the idea that TZDs spur the kidneys to hang onto salt. Normal animals excreted less sodium after TZD treatment, whereas in modified animals TZD treatment didn't alter quantities of sodium in the urine. Next, the team removed kidney cells from animals with and without PPAR{gamma} and assessed their ability to absorb sodium. TZD treatment boosted sodium uptake in normal cells but had no effect on cells without PPAR{gamma}. Together, the findings suggest that TZDs cause fluid retention by prodding PPAR{gamma} in the kidney, which enhances sodium absorption.

"Fluid retention is a serious side effect, and any way to minimize it would be a big advance," says endocrinologist Arshag Mooradian of Saint Louis University in Missouri. Researchers should now look for drugs that activate PPAR{gamma} in tissues such as fat but not in the kidney. Such compounds might stem the flood into tissues, he says. To aid the search, scientists could hunt for proteins that collaborate with PPAR{gamma} in one tissue but not another. Such drugs might not completely eliminate the problem, however. Mooradian notes that the engineered animals still held some excess fluid, suggesting that the other mechanisms contribute to bloating. Grappling with these questions might reveal ways to get a handle on blood sugar without putting extra pressure on the body.


June 22, 2005
  1. H. Zhang et al., Collecting duct-specific deletion of peroxisome proliferator-activated receptor {gamma} blocks thiazolidinedione-induced fluid retention. Proc. Natl. Acad. Sci. U.S.A., 14 June 2005 [e-pub ahead of print]. doi:10.1073/pnas.0501744102 [Abstract/Free Full Text]
Citation: R. J. Davenport, Releasing the Pressure. Sci. Aging Knowl. Environ. 2005 (25), nf47 (2005).








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