'Knockout' mouse may lead to major understanding of human kidney disorder

August 30, 1999

A basic science advance has provided a major clue to the possible cause and treatment of IgA nephropathy, a kidney disorder that affects hundreds of millions of people throughout the world. The advance, appearing in the September issue of Nature Medicine, represents what may be one of the most promising applications of "gene knockout" technology to date.

The study was conducted by scientists at the Heritable Disorders Branch of the National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), and Baylor College of Medicine. The finding builds upon a previous advance, the development of mice strains lacking the gene for a substance known as uteroglobin. In that study, the resultant mice were found to have malfunctioning kidneys due to clogged glomeruli, the kidney's filtering apparatus.

In the Nature Medicine article, the group has since determined that this kidney malfunction closely mimics the human disease, IgA nephropathy. The researchers also prevented the disorder in the mice by supplying the deficient animals with the uteroglobin normally made by the non-functioning gene.

"This mouse model matches the human form of IgA nephropathy very closely," said NICHD Director Duane Alexander, M.D. "It has provided us with very specific strategies for possibly determining the cause of the human condition and ultimately designing a treatment for it."

IgA nephropathy is the most common primary kidney glomerular disease in the world. In the U.S., more than 3,000 cases occur each year, explained the study's first author, Feng Zheng, M.D., who was at the NICHD when the study was conducted. However, in other areas, such as Japan, parts of Europe, and Australia, the disease may cause 35-40 percent of all primary glomerulopathies.

Briefly, IgA (Immunoglobin A) nephropathy results from deposits of IgA inside the kidneys. (IgA is an antibody, an immune system protein that protects against disease-causing organisms). Specifically, the disease results from the accumulation of IgA, along with the proteins fibronectin and collagen, inside the glomeruli. Normally, the glomeruli filter wastes and excess water from the blood. With IgA nephropathy, however, the deposits block the filtering process, causing blood and protein to appear in the urine as well as swelling of the hands and feet. The disease may worsen over a period of 10 to 20 years, and IgA patients may eventually require dialysis or kidney transplantation. However, in the majority of patients who undergo transplantation, the disease re-occurs in the transplanted kidneys. Currently, researchers do not know what causes the condition or how to cure it.

In the Nature Medicine article, the researchers found that injecting the uteroglobin- deficient mice with IgA caused abnormal deposition of IgA, fibronectin, and collagen in the animals' glomeruli, mirroring what occurs in the human disease. However, when injected with IgA mixed with uteroglobin, the animals failed to develop the condition.

"These results indicate that one of the essential functions of uteroglobin is to prevent abnormal IgA-deposition and consequently, the IgA-nephropathy in mice," said the study's senior author, Anil B. Mukherjee, M.D., Ph.D., of NICHD and the senior author of the study.

Dr. Mukherjee said he and his colleagues next plan to test people with IgA-nephropathy to learn if their blood uteroglobin levels differ from those of people who do not have the disease. If their uteroglobin levels are indeed found to be abnormally low, treatment might involve supplementation with uteroglobin.

Although promising, the research results need to be confirmed in human patients. At times, animal models for diseases have appeared promising and then later found to differ from the human conditions they were designed to imitate.

In the Nature Medicine article, the researchers also described a possible mechanism by which uteroglobin may prevent IgA-nephropathy in their mouse model. Dr, Mukherjee theorized that, in the absence of uteroglobin, fibronectin binds to IgA molecules, to other fibronectin molecules, as well as to molecules such as collagen. Apparently, these molecular complexes are too large to be filtered through the glomeruli, where they soon form deposits. Under normal situations, uteroglobin apparently binds to fibronectin and prevents the formation of such complexes.

The group published their original article on the gene knockout technique preventing the uteroglobin gene from functioning in the May 30, 1997 issue of Science. For technical reasons, the group had failed to detect IgA in the mice's glomeruli. At the time, the group had also thought it might be necessary to develop a second strain of mice that had low levels of uteroglobin but that were not totally deficient in the protein.

"We feared that mice lacking the functional uteroglobin gene might die during their early fetal stages," said NICHD's Zhongjian Zhang, Ph.D., a co-author of the Nature Medicine article. "For this reason, we also prevented uteroglobin production in a mouse model by using anti-sense technology."

With anti-sense technology, reverse copies of the hereditary material RNA were used to halt uteroglobin production in other mice. After refining their methods, the researchers found that the antisense mice also accumulate large amounts of IgA in their glomeruli.
More information on IgA nephropathy is available from the website of the National Institute of Diabetes and Digestive and Kidney Diseases, at: www.niddk.nih.gov/health/kidney/summary/iganeph/iganeph.htm

The NICHD is one of the Institutes comprising the National Institutes of Health, the Federal government's premier biomedical research agency. NICHD supports and conducts research on the reproductive, neurobiological, developmental, and behavioral processes that determine and maintain the health of children, adults, families, and populations. The NICHD website, www.nichd.nih.gov , contains additional information about the Institute and its mission.

The NCI is the principal government agency in the United States for research on cancer.

NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development

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