Researchers showed that breakdown of this self-cleaning feature can make kidneys more vulnerable to dysfunction and disease.
"We speculate that defects of this clearance mechanism can leave things on the filter that can damage it," says senior author Andrey Shaw, M.D., Emil R. Unanue Professor of Immunobiology in Pathology and Immunology. "This could include autoimmune antibodies that mistakenly target the body's own tissues like those that occur in the disease lupus."
The study appears in the Jan. 22 Proceedings of the National Academy of Sciences.
Despite extensive knowledge of the structure of the kidney, several scientific controversies linger over how the organ does its complicated and essential job of filtering wastes from the blood for disposal without simultaneously discarding too much water or key blood proteins in the urine. Understanding how these tricky tasks are accomplished is essential to developing new treatments for kidney disease and renal failure, which are among the top ten causes of death in the United States.
Like many mechanical filtering systems, the kidney passes the blood through a series of progressively finer screens. After passing through a structure known as the glomerular basement membrane (GBM), fluid and serum proteins must finally pass through the most selective filter of the kidney, which is comprised of specialized epithelial cells called podocytes. These cells form a web-like barrier to the passage of large serum proteins into the urine.
"The kidney screens 150 to 200 liters of blood daily, and we were curious as to how the kidney keeps the filter from clogging up," says first author Shreeram Akilesh, an M.D./Ph.D. student. "The two most common blood serum and plasma proteins are albumin, which helps regulate blood volume and convey a number of different substances around the body, and immunoglobin G (IgG), a type of immune system antibody. Because they're so common, we figured they would be among the most likely to get stuck on the filter, and set out to look for proteins that help clear them."
Researchers looked for proteins made in podocytes that could bind to albumin and IgG, reasoning that such proteins likely provide the "handles" the podocytes need to grab proteins and clear them from the filter.
A protein known as FcRn was high on the list of likely suspects. Akilesh had studied FcRn previously in the laboratory of coauthor Derry C. Roopenian, Ph.D., professor at the Jackson Laboratory in Bar Harbor, Maine. Prior research there and in other laboratories had revealed that FcRn binds to both IgG and albumin and is present in human podocytes.
After confirming that the FcRn protein also is made in mouse podocytes, scientists then asked if FcRn was responsible for clearing IgG antibody from the filter. To do this, they measured the retention of a radioactive tracer in the kidneys of normal mice and in mice where the gene for FcRn had been disabled. Mice lacking FcRn had difficulty clearing antibody from the kidney.
When researchers studied the mice lacking FcRn for longer periods of time, they saw evidence that antibodies were accumulating in the kidney.
In another experiment, researchers gave the mice injections of large quantities of protein to saturate the clearance system. They followed those injections with what would normally have been a harmlessly small dose of an antibody potentially toxic to the kidney. The mice developed kidney damage as a result. Researchers believe this was because they couldn't clear the toxic antibody from the GBM quickly enough.
"This is the first clear demonstration that the filter system in the kidney isn't just a passive mechanical filter, it's actually involved in its own maintenance," says Akilesh. "It also provides us with a nice mechanism for explaining how the normal function of this filter may be breaking down in ways that leads to kidney disease and damage."
To follow up, Shaw plans to look for other podocyte proteins involved in filter clearance.
Michael C. Purdy | EurekAlert!
WAKE-UP provides new treatment option for stroke patients | International study led by UKE
17.05.2018 | Universitätsklinikum Hamburg-Eppendorf
First form of therapy for childhood dementia CLN2 developed
25.04.2018 | Universitätsklinikum Hamburg-Eppendorf
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...
02.05.2018 | Event News
13.04.2018 | Event News
12.04.2018 | Event News
24.05.2018 | Ecology, The Environment and Conservation
24.05.2018 | Medical Engineering
24.05.2018 | Physics and Astronomy