Kidney-damaging protein offers clue to new treatment

November 17, 2005

CINCINNATI--Scientists led by a University of Cincinnati (UC) kidney expert have found that a naturally occurring protein that normally fights cancer cells can also cause severe kidney failure when normal blood flow is disrupted.

This finding, seen in mice in which the gene controlling the protein is actually expressed or "turned on," could provide a target for drugs that will reduce the risk of kidney damage in humans, the researchers believe.

Acute kidney failure is a life-threatening illness caused by sudden, severe loss of blood flow to the kidneys (ischemia). Despite advances in supportive care, such as dialysis, severe kidney injury is a major cause of death.

The scientists, headed by Manoocher Soleimani, MD, director of nephrology and hypertension at UC and the Cincinnati Veterans Affairs Medical Center, report their findings in the Dec. 1, 2005, issue of the Journal of Clinical Investigation.

The protein, thrombospondin (TSP-1), is known for its role in fighting cancer. It does this by killing off cancer cells and preventing the tumor from building a greater blood supply.

Although TSP-1 causes irreversible, severe kidney damage when blood flow to mouse kidneys is disrupted, the researchers say, this only occurs in animals whose TSP-1 gene is turned on.

The study showed that the protein damages kidney cells when blood flow is reduced for 30 minutes or more. When blood flow is restored to the kidneys, if TSP-1 protein is present, normal kidney function doesn't return.

"This raises the important possibility that TSP-1 may serve as a target in preventing or successfully treating acute kidney failure," said Dr. Soleimani. "Understanding the mechanisms of kidney cell injury moves us that much closer to preventing this life-altering damage from happening.

"If we can develop a drug that will inhibit or turn off the TSP-1 gene function, then severe kidney damage could be prevented--even during a 30-minute disruption in blood flow," he said.

"Since the incidence of death remains high in patients with damaged kidneys, prevention or early treatment of acute kidney failure will increase survival."

The study showed that the damaging protein is released rapidly, in response to diminished blood flow, in mice that have the active TSP-1 gene. TSP-1 also killed kidney cells when exposed to them in a Petri dish.

"Most importantly," Dr. Soleimani said, "we found that genetically engineered mice, which lack TSP-1 protein, were significantly protected from kidney damage. Mice without TSP-1 preserved their kidney function relatively well, even after being subjected to a 30-minute disruption of blood flow to the kidneys.

"Consequently, this study raises an important possibility that TSP-1 may serve as a target for preventing or successfully treating acute kidney failure," Dr. Soleimani said.
-end-
Co-authors included UC's Charuhas Thakar, MD, Zhauhui Wang, PhD, Sharon Barone and Charles Burnham, PhD, of internal medicine, Monica Revelo, MD, pathology, Alex Lentsch, PhD, surgery, and Kamyar Zahedi, PhD, UC pediatrics and Cincinnati Children's Hospital Medical Center, and Hamid Rabb, MD, of Johns Hopkins University.

University of Cincinnati

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