The mouse study, published in the Sept. 1 issue of The Journal of Immunology, indicates that knocking out the normal function of certain enzymes can protect the kidney from damage and inflammation following blood flow blockage. Such damage affects patients with conditions such as diabetes and acute renal failure, and can destroy kidneys taken from cadavers for transplant.
The enzymes in question are called fucosyltransferases. During injury repair, they add the sugar fucose to proteins that allow white blood cells to bind to the sites of damage. Developing drugs that target the fucose or the fucosyltransferase enzyme could lead to new therapies to stop blood flow blockage in the kidneys, as well as heart and brain, says senior author Hamid Rabb, M.D., medical director of the kidney transplant program at Hopkins.
"This opens up a new line of research on the therapeutic potential of sugars, which are more readily available naturally and may have fewer side effects than conventional drugs," he says.
Researchers compared normal mice with those genetically altered to lack one of two forms of fucosyltransferase, abbreviated FucT-IV and FucT-VII, or to lack both. To mimic natural injury, the scientists clamped blood vessels in the animals' kidneys for 30 minutes, then measured kidney function, and structural and molecular changes to the organs 24, 48 and 72 hours after surgery.
Normally, the body calls on white blood cells to fight infection. One type of white blood cell, the neutrophil, destroys bacteria and parasites by traveling to the site of invasion and engulfing its foe. But sometimes the white blood cells mistake the "on" signal and continue to attack tissue after damage is repaired, causing inflammation and additional damage in the process.
In the Hopkins study, mice deficient in both fucosyltransferase enzymes were significantly protected against kidney dysfunction and damage after injury, and had a reduced number of neutrophils at the injury site, compared to normal mice. The mice deficient only in FucT-IV were also significantly protected from injury, but not as much as those deficient in both enzymes.
"These data demonstrate that the fucosyltransferase enzyme family represents important mediators of kidney dysfunction and structural injury after an episode of decreased blood flow," says lead author Melissa J. Burne. "The findings have implications for research into conditions like heart attacks and strokes, which have similar blood flow blockages."
More than 20 million Americans have chronic kidney disease, according to the National Kidney Foundation. About 52,000 are on the wait list for a kidney transplant.
The research was supported by the National Kidney Foundation and the National Institutes of Health.
Burne, M.J., and Hamid Rabb, "Pathophysiological Contributions of Fucosyltransferases in Renal Ischemia Reperfusion Injury," The Journal of Immunology, Sept. 1, 2002, Vol. 169, pages 2648-2652.
Related Web sites:
Johns Hopkins Division of Nephrology
http://www.hopkinsmedicine.org/nephrology
Johns Hopkins Comprehensive Transplant Center
http://www.hopkinsmedicine.org/transplant
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Journal
The Journal of Immunology