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The kidneys – intelligent filtration
The kidneys clean an average of five million litres of blood during a person’s lifetime.
Besides the heart, the kidneys are one of the most essential organs in the human body. The
blood is filtered in microscopically small renal corpuscles which divert toxins or metabolic
degradation products to the urethra through a thin membrane. Dr. Tobias Huber and his
team at the Freiburg University Medical Centre are investigating the molecular processes
that occur at this so-called slit diaphragm. The researchers were able to show that the renal
corpuscles are at the centre of a highly “intelligent” process, rather than being just a purely
passive filter.
Around four to five thousand litres of blood flow through the human kidneys every day. The
blood contains toxic molecules taken up with food and/or metabolic degradation products that
the human body wants to get rid of. But the kidneys can do a lot more: they also ensure that
the blood does not become too diluted and that the concentration of dissolved salts is kept at
an appropriate level. The kidneys are a filter that cleans the human blood by withdrawing toxic
or no longer needed substances and excreting them in the form of urine. The kidneys are
highly selective and very sensitive. They “know” exactly how much salt needs to be withdrawn
from the blood in order to maintain vital salt levels. In addition, the renal filter retains proteins
(e.g., enzymes) dissolved in the blood, which are still required by the organism. “In my lectures I
often say that the kidneys are the actual brain of humans,” said Dr. Tobias Huber from the
Department of Nephrology at the Freiburg University Medical Centre, adding “well, of course
that’s not quite true, but it is important to highlight the key role played by the kidneys as often
as possible.”
Intoxication from the inside
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The renal filter consists of three layers: the endothelial cells coating the blood vessel, the glomerular basal
membrane (GBM) and the long foot projections of the podocytes which wrap around the capillaries, leaving slits
between them. © Dr. Tobias Huber
The importance of the key role played by the kidneys becomes all too clear when kidney failure
occurs due to damage or disease. The American healthcare system, for example, spends
around twenty billion dollars on dialysis patients every year. People with kidneys that no longer
function properly are obliged to undergo renal dialysis three times per week. Dialysis is a
procedure that replaces kidney function, in which the blood is pumped through an artificial
filter to remove toxic products and impurities. "The number of people requiring dialysis is
constantly increasing," said Huber. Kidney failure leads to an imbalance in the composition of
body fluids, which means that the body is intoxicated from the inside. "In the majority of people
suffering from renal insufficiency, the disease is the result of a defect of the slit diaphragm or
the cells surrounding it," said Huber explaining that his independent Emmy Noether research
group is focusing on the molecular processes in these active filtration zones to shed light on
why damaged slit diaphragms have such far-reaching consequences.
The slit diaphragm is part of a complex system consisting of cell and molecular layers wrapped
around the arteries of the so-called renal corpuscles. The renal corpuscles are small bodies
with a fine network of small blood vessels that make contact with the urethras. In humans,
each kidney has around one million renal corpuscles. The walls of the arteries are coated with
endothelial cells (cells that form a tight wall coating in other organs as well), which in turn are
covered by a layer of proteins and long-chain sugar molecules. This layer is referred to as basal
lamina. Podocytes are located on the basal lamina in a way that resembles the shape of an
octopus. The tentacles (i.e., feet, which is where the name podocytes comes from) of the
podocytes interdigitate with the tentacles of neighbouring podocytes. The slits between the
individual podocyte feet are bridged by a protein layer that is known as a slit diaphragm. The
blood is pressed through all these layers. Each layer retains a particular group of important
molecules and lets the remaining liquid pass through. At the end of the filtration process,
primary urine enters the urethras.
Vital function
“What is the role of the slit diaphragm and the podocytes in terms of filtration?” asks Huber.
“Are they purely mechanical filters?” Huber’s team have been studying the central proteins
that form the slit diaphragm for a number of years. These proteins are molecules of the NephNephrin protein family produced by the podocytes that are anchored in the cell membrane of
the podocytes. The Neph-Nephrin proteins extend into the extracellular space and bind similar
proteins originating from neighbouring podocytes, thus forming the protein layer which the
scientists refer to as slit diaphragm. The slit diaphragm is an extremely vital zone. The
experiments carried out by Huber’s team have shown that the proteins that form the slit
diaphragm detect a broad range of environmental stimuli and transfer this information into
the podocytes. In a collaborative project with Marty Chalfie, who received the Nobel Prize in
Chemistry in 2008, Huber’s team was able to show that the slit diaphragm is a mechanical
sensor, which constantly measures the filtration rate and reports back to the interior of the
podocytes.
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Scanning electron microscope images (A) of a renal corpuscle (consisting of a glomerulus and a Bowman's capsule),
(B) a blood vessel inside the renal corpuscle, (C) the endothelium, (D) a podocyte, (E) podocyte protrusions, (F) a
cross-section of the filter layers (blood side on the left and urine side on the right). © Dr. Tobias Huber
The slit diaphragm not only ensures that the cells adapt morphologically to the filter load. The
importance of the slit diaphragm becomes particularly obvious in a clinical context: Damaged
or destroyed diaphragms (for example as a result of a genetic defect or inflammation) are no
longer able to send survival signals to the podocytes. These signals normally prevent the cells
from initiating processes that lead to programmed cell death (apoptosis). Therefore, the
podocytes die, resulting in the scarring and death of the renal corpuscles. The more corpuscles
that die, the less effective the kidneys become, eventually requiring dialysis.
Team spirit and excellent research
“During the past few years, we have identified many signalling programmes that regulate the
filtering processes of the slit diaphragm,” said Huber. “At present we are looking for answers
to the questions as to how these signalling programmes lead to the development of the slit
membrane and podocytes, how they maintain their correct function and what happens during
disease?” An answer to the last question might in future open up new approaches in the
therapy of kidney diseases that are associated with a defect of the renal corpuscles. In order to
gain detailed insights into these processes, Huber and his team are investigating genetic
mouse models and are working with other research groups that investigate similar principles
using other model organisms (e.g., fruit flies (Drosophila), C. elegans). Neph-Nephrin proteins
are also found in many other organisms, including humans. Huber puts the success of his
research down to team spirit and flat hierarchies as well as to the exchange of information
with other specialists. “Here in Freiburg, the Department of Nephrology established by Prof.
Gerd Walz provides a unique density of different ideas and technical know-how,” said Huber. “I
believe that team spirit is paramount for carrying out excellent research.”
Further information:
PD Dr. Tobias Huber
Medicine IV, Nephrology
Freiburg University Medical Centre
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Tel: +49 (0)761/270-3559
E-mail: tobias.huber(at)uniklinik-freiburg.de
Article
17-May-2010
mn
BioRegion Freiburg
© BIOPRO Baden-Württemberg GmbH
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