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 New combination therapy established as safe and effective for prostate cancer
26.06.2019 | Society of Nuclear Medicine and Molecular Imaging

nachricht Novel model for studying intestinal parasite could advance vaccine development
26.06.2019 | University of Pennsylvania

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: Fraunhofer IDMT demonstrates its method for acoustic quality inspection at »Sensor+Test 2019« in Nürnberg

From June 25th to 27th 2019, the Fraunhofer Institute for Digital Media Technology IDMT in Ilmenau (Germany) will be presenting a new solution for acoustic quality inspection allowing contact-free, non-destructive testing of manufactured parts and components. The method which has reached Technology Readiness Level 6 already, is currently being successfully tested in practical use together with a number of industrial partners.

Reducing machine downtime, manufacturing defects, and excessive scrap

Im Focus: Successfully Tested in Praxis: Bidirectional Sensor Technology Optimizes Laser Material Deposition

The quality of additively manufactured components depends not only on the manufacturing process, but also on the inline process control. The process control ensures a reliable coating process because it detects deviations from the target geometry immediately. At LASER World of PHOTONICS 2019, the Fraunhofer Institute for Laser Technology ILT will be demonstrating how well bi-directional sensor technology can already be used for Laser Material Deposition (LMD) in combination with commercial optics at booth A2.431.

Fraunhofer ILT has been developing optical sensor technology specifically for production measurement technology for around 10 years. In particular, its »bd-1«...

Im Focus: The hidden structure of the periodic system

The well-known representation of chemical elements is just one example of how objects can be arranged and classified

The periodic table of elements that most chemistry books depict is only one special case. This tabular overview of the chemical elements, which goes back to...

Im Focus: MPSD team discovers light-induced ferroelectricity in strontium titanate

Light can be used not only to measure materials’ properties, but also to change them. Especially interesting are those cases in which the function of a material can be modified, such as its ability to conduct electricity or to store information in its magnetic state. A team led by Andrea Cavalleri from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg used terahertz frequency light pulses to transform a non-ferroelectric material into a ferroelectric one.

Ferroelectricity is a state in which the constituent lattice “looks” in one specific direction, forming a macroscopic electrical polarisation. The ability to...

Im Focus: Determining the Earth’s gravity field more accurately than ever before

Researchers at TU Graz calculate the most accurate gravity field determination of the Earth using 1.16 billion satellite measurements. This yields valuable knowledge for climate research.

The Earth’s gravity fluctuates from place to place. Geodesists use this phenomenon to observe geodynamic and climatological processes. Using...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on UV LED Technologies & Applications – ICULTA 2020 | Call for Abstracts

24.06.2019 | Event News

SEMANTiCS 2019 brings together industry leaders and data scientists in Karlsruhe

29.04.2019 | Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

 
Latest News

Shell increases versatility of nanowires

26.06.2019 | Materials Sciences

Hubble finds tiny 'electric soccer balls' in space, helps solve interstellar mystery

26.06.2019 | Physics and Astronomy

New combination therapy established as safe and effective for prostate cancer

26.06.2019 | Health and Medicine

VideoLinks
Science & Research
Overview of more VideoLinks >>>