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 Biofilm discovery suggests new way to prevent dangerous infections
23.05.2017 | University of Texas at Austin

nachricht Another reason to exercise: Burning bone fat -- a key to better bone health
19.05.2017 | University of North Carolina Health Care

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: Can the immune system be boosted against Staphylococcus aureus by delivery of messenger RNA?

Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.

Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....

Im Focus: A quantum walk of photons

Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.

The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....

Im Focus: Turmoil in sluggish electrons’ existence

An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.

We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...

Im Focus: Wafer-thin Magnetic Materials Developed for Future Quantum Technologies

Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.

Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...

Im Focus: World's thinnest hologram paves path to new 3-D world

Nano-hologram paves way for integration of 3-D holography into everyday electronics

An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Marine Conservation: IASS Contributes to UN Ocean Conference in New York on 5-9 June

24.05.2017 | Event News

AWK Aachen Machine Tool Colloquium 2017: Internet of Production for Agile Enterprises

23.05.2017 | Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

 
Latest News

How herpesviruses win the footrace against the immune system

26.05.2017 | Life Sciences

Water forms 'spine of hydration' around DNA, group finds

26.05.2017 | Life Sciences

First Juno science results supported by University of Leicester's Jupiter 'forecast'

26.05.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>