The CT
image reveals the presence of kidney stones. New research at Washington
University School of Medicine in St. Louis provides evidence to explain why
some people are more prone to the condition than others. Credit: Alana Desai,
MD, Washington University in St. Louis
Kidney stones strike an estimated 1 million
Americans each year, and those who have experienced the excruciating pain say
it is among the worst known to man (or woman).
Now,
new research by scientists at Washington University School of Medicine in St.
Louis provides evidence to explain why some people are more prone to develop
the condition than others. Their discovery opens the door to finding effective
drug treatments and a test that could assess a person's risk of kidney stones.
"Now,
we finally have a more complete picture detailing why some people develop
kidney stones and others do not," says senior author Jianghui Hou, PhD,
assistant professor of medicine. "With this information, we can begin to
think about better treatments and ways to determine a person's risk of the
condition, which typically increases with age."
The
research, in mice, is now available online in the EMBO Journal,published
by the European Molecular Biology Organization.
Because
kidneys function the same way in mice as in humans, the new
findings can help scientists understand
the root causes of kidney stones in patients. The mouse model used in
the study can also serve as a platform for the preclinical testing of novel
treatments for the condition, the researchers say.
Most
kidney stones form when the urine becomes too concentrated, allowing minerals
like calcium to
crystallize and stick together. Diet plays a role in the
condition — not drinking enough water or eating too much salt (which binds to
calcium) also increases the risk of stones.
But
genes are partly to blame. A common genetic variation in a gene called
claudin-14 recently has been linked to a substantial increase in risk — roughly
65 percent — of getting kidney stones. In the new study, the researchers have
shown how alterations in the gene's activity influence the development of
stones.
Typically,
the claudin-14 gene is not active in the kidney. The new research shows that
its expression is dampened by two snippets of RNA, a sister molecule of DNA,
that essentially silence the gene.
When
claudin-14 is idled, the kidney's filtering system works like it's supposed to.
Essential minerals in the blood like calcium and magnesium pass through the
kidneys and are reabsorbed back into the blood, where they are transported to
cells to carry out basic functions of life.
But
when people eat a diet high in calcium or salt and don't drink enough water,
the small RNA molecules release their hold on claudin 14. An increase in the
gene's activity prevents calcium from re-entering the blood, the study shows.
Hou and
his team have found that claudin-14 blocks calcium from entering passageways
called tight junctions in cells that line the kidney and separate blood from
urine.
Without
a way back to the bloodstream, excess calcium goes into the urine. Too much
calcium in the urine can lead to stones in the kidneys or bladder. Intense pain
develops when a large stone gets stuck in the bladder, ureter or urethra and
blocks the flow of urine.
Hou's
research supports the theory that people with a common variation in claudin-14
lose the ability to regulate the gene's activity, increasing the risk of kidney
stones.
He is
optimistic, however, that drugs could be developed to target the short
stretches of RNA that are intimately linked to claudin 14. Drugs that mimic
these so-called microRNAs could keep the activity of claudin-14 in check and
reduce the likelihood that stones would form.
Also,
it may one day be possible to develop a diagnostic test to measure levels of
the claudin-14 protein excreted in urine. Elevated levels would indicate an
increased risk of stones, and people could take steps to prevent stones by
modifying their diet.
"Many
genes likely play a role in the formation of kidney stones," Hou says.
"But this study gives us a better idea of the way one of the major players
work. Now that we understand the physiology of the condition, we can start to
think about better treatments or even ways to prevent stones from developing in
the first place."
More
information: Gong
Y, Renigunta V, Himmerkus N, Zhang J, Renigunta A, Bleich M, Hou J. Claudin-14
regulates renal CA++ transport in response to CaSR signaling via a novel
microRNA pathway. The EMBO Journal. Advance online publication Feb.
28, 2012.
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