Bethesda,
MD (8/30/99)- Researchers now have a better understanding of the cause
of one of the most common forms of kidney disease as well as a potential cure,
thanks to a mouse with a single missing gene.
IgA nephropathy is a kidney disorder that affects millions of people around
the world. The disease is caused when IgA (immunoglobulin A) blocks glomerular
filtering within the kidney. Over time the kidney looses its ability to function,
meaning that patients may require dialysis or kidney transplantation.
Scientists at the Heritable Disorders Branch of the National Institute of
Child Health and Human Development (NICHD) determined that genetically engineered
mice lacking the gene for a substance known as uteroglobin developed the renal
malfunctioning characteristic of IgA nephropathy. They then found that supplying
the 'knockout' mice with the uteroglobin normally made by the nonfunctioning
gene prevented the disorder from developing. More recently, the researchers
discovered that disease in mice closely resembles the human form of the disease.
"This mouse model matches the human form of IgA nephropathy very closely,"
"It has provided us with very specific strategies for possibly determining
the cause of the human condition and ultimately designing a treatment for
it." said NICHD Director Duane Alexander, M.D.
The researchers believe the findings may point to a possible mechanism by
which uteroglobin may prevent IgA-nephropathy in their mouse model. They believe
that, in the absence of uteroglobin, fibronectin binds to IgA molecules, to
other fibronectin molecules, as well as to molecules such as collagen. Because
these molecular complexes are too large to be filtered through the glomeruli,
they form deposits, preventing filtration. When uteroglobin is present, it
appears to bind to fibronectin, preventing formation of the deposits that
clog the system. .
The research group confirmed the findings by using two different genetic
manipulation techniques. First they took advantage of 20 years worth of experience
with knockout gene experimentation to produce a mouse lacking the uteroglobin
gene. However, for technical reasons, the group had failed to detect IgA in
the mice's glomeruli.
"We feared that mice lacking the functional uteroglobin gene might die during
their early fetal stages. For this reason, we also prevented uteroglobin production
in a mouse model by using anti-sense technology," said NICHD researcher Zhongjian
Zhang, Ph.D.
By utilizing anti-sense technology, reverse copies of the hereditary material
RNA were used to halt uteroglobin production in other mice. After refining
their methods, the researchers found that the antisense mice also accumulate
large amounts of IgA in their glomeruli.
The researchers hope to test people with IgA-nephropathy to learn if their
blood uteroglobin levels differ from those of people who do not have the disease.
If the patients' uteroglobin levels are indeed found to be abnormally low,
treatment might involve supplementation with uteroglobin.
IgA nephropathy is the most common primary kidney glomerular disease in the
world. In the U.S., more than 3,000 cases occur each year. However, in other
areas, such as Japan, parts of Europe, and Australia, the disease may cause
35-40 percent of all primary glomerulopathies.
The research appears in the September 1999 issue of Nature Medicine,
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