Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mouse model offers new explanation for kidney disease and failure

23.05.2003


Mice lacking only one copy of the gene for CD2-associated protein (CD2AP) appear to be significantly more susceptible to kidney disease and failure than normal mice. Moreover, the mutation appears to impair the elimination of proteins that accumulate in the kidney, a previously unidentified process.



The study, which will be published in the May 23 issue of the journal Science, is the first to suggest that proteins normally pass into the kidneys and that kidney disease may result from an inability to draw them back out. It also identifies at least two patients with kidney disease who lack one copy of CD2AP, suggesting that this mutation may be responsible for illness in some humans.

"Most experts believe that kidney disease is caused by an immune response against the kidney," explains principal investigator Andrey S. Shaw, M.D., professor of pathology and immunology at Washington University School of Medicine in St. Louis. "But our evidence suggests that defects that are intrinsic to the kidney also contribute to kidney failure."


Millions of people suffer from kidney disease and, according to the National Institute of Diabetes and Digestive and Kidney Diseases, more than 65,000 Americans die of end-stage kidney failure every year. While several genes recently have been identified as potential factors, the mechanisms that contribute to disease development are poorly understood.

In 1999, Shaw’s team discovered that mice completely lacking CD2AP quickly develop kidney disease and die from kidney failure after about six weeks. The results suggest that this protein is critical for the kidneys to function, but the researchers recognized that very few humans are likely to be missing both copies of this gene. So they examined the effects of missing only one copy.

After about nine months, mice with only one copy of CD2AP appeared healthy but, when examined after death, they had abnormalities in their glomeruli, the clusters of miniscule blood vessels where blood is filtered to excrete waste in the urine. These abnormalities were similar to those seen in 3-week-old mice lacking both copies of the gene.

In addition, when injected with toxic proteins to simulate kidney stress, two-thirds of these mice developed clinical signs of kidney disease compared to only 7 percent of normal mice. And while normal mice recovered within two weeks, mice lacking one copy of CD2AP had more severe and persistent symptoms that were fatal in some of the animals.

"Missing one copy of a gene is far more common than missing both copies, so the fact that animals who still have one healthy copy of this gene also develop disease implies that this defect could be responsible for a greater number of cases in patients," Shaw says. "Our results suggest that it’s possible that an individual with only one copy of this gene can function normally in general, but that a chronic illness, stress or even advanced age might trigger kidney failure in someone with only one functional copy."

According to Shaw, the most intriguing finding from this study is why the mice developed kidney disease. Despite the widely accepted belief that blood proteins do not pass through the kidney’s blood filter, Shaw’s team discovered that some kidney cells in mice lacking one copy of CD2AP had accumulated antibodies from the blood, proteins normally produced by the immune system in response to infection.

The researchers found no immunological abnormalities in these mice that could account for the antibody accumulation. By injecting a tracer that allowed them to watch as proteins moved through the blood into the kidney, they found evidence that CD2AP functions to route proteins for degradation. They therefore propose that proteins from the blood routinely flux into the blood filters of the kidney, but that they normally are quickly removed and therefore undetectable. When aging or stress conditions elevate protein levels in mice without enough CD2AP, defects in the clearance mechanism may prevent proteins from adequately being cleared out.

"It’s generally thought that the presence of antibodies in the kidney indicates a problem with the immune system," Shaw says. "But our data suggest that antibodies and other proteins from the blood may normally pass through or become trapped in the filters of the kidney and that an important process is the removal or clearance of these proteins from the kidney."

The glomerular abnormalities in mice lacking one copy of CD2AP are very similar to a disease in humans called focal segmental glomerulosclerosis (FSGS), one of the most common forms of kidney disease. FSGS afflicts both children and adults, is more prevalent in African Americans and can be triggered by chronic infections such as HIV. Currently, the disease has no treatment or cure.

Shaw and his colleagues examined DNA from 45 African Americans with FSGS, 15 of whom also had HIV. They compared these individuals with 45 African Americans with HIV who did not have kidney problems. Ten of the individuals with FSGS had DNA changes in the CD2AP gene that were not found in the control group. Two of these patients had a genetic mutation that would be expected to block one of the two copies of their CD2AP gene, consistent with the idea that inheriting only one copy of the gene can lead to kidney disease.

"I think there are going to be many genes identified in the future that are involved in the clearance of these proteins from the kidney," Shaw says. "In this case, we identified at least two patients that lack one copy of CD2AP. We hope that more knowledge about such mutations will help us identify individuals predisposed to develop these diseases and potentially prevent them from becoming sick."


Kim JM, Wu H, Green G, Winkler CA, Kopp JB, Miner JH, Unanue ER, Shaw AS. CD2-associated protein hapoinsufficiency is linked to glomerular disease susceptibility. Science, May 23, 2003.

Funding from the National Institute of Diabetes and Digestive and Kidney Diseases supported this research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Gila Z. Reckess | EurekAlert!
Further information:
http://medinfo.wustl.edu/

More articles from Health and Medicine:

nachricht Penn study identifies new malaria parasites in wild bonobos
21.11.2017 | University of Pennsylvania School of Medicine

nachricht NIST scientists discover how to switch liver cancer cell growth from 2-D to 3-D structures
17.11.2017 | National Institute of Standards and Technology (NIST)

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Nanoparticles help with malaria diagnosis – new rapid test in development

The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.

Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

From Hannover around the world and to the Mars: LZH delivers laser for ExoMars 2020

21.11.2017 | Physics and Astronomy

Borophene shines alone as 2-D plasmonic material

21.11.2017 | Materials Sciences

Penn study identifies new malaria parasites in wild bonobos

21.11.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>