Protein May Be Key to Kidney Health : Medicine: Researchers also believe findings may lead to treatments for diseases where organs are destroyed by scarring.
San Diego and Utah researchers have identified a naturally occurring human protein that prevents kidney disease in rats, a development they say could play a key role in preventing kidney failure in humans.
The discovery could hold promise for treating several other deadly diseases where organs are destroyed by scarring, according to researchers at the La Jolla Cancer Research Foundation, Telios Pharmaceuticals and the University of Utah.
In today’s issue of the British journal Nature, the research team reported that decorin, a naturally occurring human protein, stops production of “transforming growth factor-beta” (TGF-B), an agent that is present in glomerulonephritis, a disease that afflicts as many as 100,000 Americans each year.
TGF-B also has been identified with kidney disease caused by diabetes. Diabetic patients accounted for 39,007 of the 137,446 Medicare patients who received dialysis during 1991.
The discovery that decorin is a natural inhibitor of TGF-B is “an encouraging development,” said Alan R. Hull, a Dallas-based doctor and vice president of the National Kidney Foundation. “They’ve taken something that once was only a test-tube phenomena and taken it to small laboratory animals . . . the next step should be dogs or apes, and in the mid-1990s, they hope to get to human testing.”
Researchers also believe that decorin’s ability to suppress production of TGF-B could lead to treatments for other diseases where organs are destroyed by pathological scarring. TGF-B’s link to liver cirrhosis, lung fibrosis and several less-common diseases is being investigated by researchers in San Diego, Utah and elsewhere.
And the La Jolla foundation, where researchers initially isolated the genetic makeup of decorin, will continue to “plug away at what (the suspected agent) means in various cancers,” Foundation President Erkki Ruoslahti said Wednesday.
Telios, a La Jolla-based pharmaceutical company, has acquired rights to patent applications filed by the La Jolla Cancer Research Foundation and the University of Utah.
Because TGF-B is evident in “virtually every other organ of the body” known to suffer severe scarring, decorin’s role as a natural inhibitor “may be the breakthrough we have been looking for,” said Wayne A. Border, chief of the nephrology division at the University of Utah School of Medicine. “We assume that decorin will not just be a kidney drug but an anti-scarring drug that will be used widely in conditions where excessive scarring is present.”
So far, research into decorin’s role as a natural inhibitor of TGF-B has focused on kidney disease.
Healthy kidneys act as a filter, removing excess water and waste from the bloodstream. But when the organs fail, patients must either receive transplants or remain on dialysis for the remainder of their lives.
About 110,000 Americans now undergo dialysis routinely to remain healthy, at an estimated annual cost of $2.5 billion nationally. Because of a donor shortage, only 9,000 of the 17,000 patients waiting for kidney transplants will receive them during 1992.
Within the kidneys, impurities are filtered out of the bloodstream by small units called glomeruli. In patients with severe cases of diabetes, high blood pressure and glomerulonephritis, the glomeruli are clogged by abnormally high amounts of a fibrous meshwork called “extracellular matrix.”
In 1990, researchers in Utah and San Diego determined that glomerulonephritis in rats was caused by excess concentrations of TGF-B. Ongoing research in Utah, San Diego and elsewhere since has linked TGF-B to kidney disease caused by glomerulonephritis and diabetes.
Two years ago, researchers in Utah and San Diego used specially formulated antibodies to inhibit growth of TGF-B in rats and control scarring. At the same time, test tube experiments proved that decorin could bind to TGF-B and neutralize it.
In today’s Nature report, researchers said that decorin injected into laboratory rats subsequently attached to TGF-B and neutralized it, preventing scarring in rats’ kidneys.
While the antibodies might one day prove suitable for use in humans, decorin holds greater promise because the naturally occurring human protein probably would not prompt allergic reactions.
“If we continued work with antibody technology, we’d have to find ways to make antibodies more tolerable to the body,” Border said. “But decorin is an enormous breakthrough.”
The extracellular matrix that plays a key role in diseases where scarring destroys organs also is believed to play a role in the development of various cancers.
When too much TGF-B is present, organs evidently suffer from a damaging accumulation of extracellular matrix and are scarred. But when too little of the matter exists, cells evidently can migrate to places where they normally wouldn’t travel--as is the case with tumor cells, Ruoslahti said.
“We’ve found ways of making the tumor cells stick better to this extracellular matrix cage,” Ruoslahti said. “Now we’re working on ways to force tumor cells to make their own cages . . . which would then limit their ability to move.”
The La Jolla Cancer Research Foundation initially investigated decorin during its ongoing attempt to better understand cancer.
The foundation will continue to research TGF-B’s suspected link to cancer, “but it’s nice to see that what we’re coming up with in basic cancer research--such as isolating the gene for decorin--can be used more immediately in other diseases,” Ruoslahti said.
