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%—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.”
The research was funded, in part, by the National Institutes of Health (NIH) and the American Heart Association.
Hou
is working with Washington University’s Office of Technology Management
on an invention related to work described in the paper.
Citation:
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.
