The findings take a major step toward suggesting a beneficial treatment for rapidly progressive glomerulonephritis (RPGN), a rare but debilitating kidney disease that causes renal failure and death in humans.
In a paper published online in Nature Medicine, the researchers show that blocking the ability of the epidermal growth factor (EGF) receptor – an important component in wound healing – to bind with certain molecules in the kidneys of mice can eliminate the harmful effects of a mimic version of RPGN.
EGF receptors act like important keyholes on a cell's surface, says Dr. David Threadgill, professor and head of NC State's Department of Genetics and a co-author of the paper. Certain keys, or in this case molecules, can fit with the receptor and "open the door" to a cascade of cellular processes leading to inflammation, which can be good when your body needs to heal a wound or a cut. It's bad, however, when the inflammation runs amok, as when RPGN takes hold.
How important are EGF receptors in RPGN? When EGF receptors were taken out of the equation – through special mice from Threadgill's lab that were genetically engineered without EGF receptors – the disease was unable to take hold and degenerate kidney tissues.
The study also showed that certain drugs that inhibit EGF receptors – think of them as pieces of gum in the keyholes – not only prevented mouse kidneys from degrading but also reversed the harmful effects four days after mice were exposed to the RPGN mimic.
"EGF receptors are essential components for life, but are implicated in not only RPGN but also a number of cancers like colon cancer and breast cancer," Threadgill says. "They must be tightly regulated. If we can inhibit these receptors for short periods of time, we may be able to stop out-of-control cell proliferation and inflammation and thus prevent or treat certain cancers or diseases."
The Department of Genetics is part of NC State's College of Agriculture and Life Sciences.
"The Epidermal Growth Factor Receptor Promotes Glomerular Injury and Renal Failure in Rapidly Progressive Crescentic Glomerulonephritis; the Identification of Possible Therapy"Authors: Martin Flamant, Universite Paris-Diderot; Guillaume Bollee, Universite Paris-Descartes; David Threadgill, North Carolina State University, et al
Published: Online Sept. 25, 2011, in Nature Medicine
Abstract: Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome and a morphological expression of severe glomerular injury. Glomerular injury manifests as a proliferative histological pattern, accumulation of T cells and macrophages, proliferation of intrinsic glomerular cells, accumulation of cells in Bowman's space ("crescents"), and rapid deterioration of renal function. Here we show de novo induction of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in intrinsic glomerular epithelial cells (podocytes) from both mice and humans with RPGN. HB-EGF induction increases phosphorylation of the EGFR/ErbB1 receptor in mice with anti-GBM disease. In HB-EGF-deficient mice, EGFR activation in glomeruli is absent and the course of RPGN is markedly improved. Autocrine HB-EGF induces a phenotypic switch in podocytes in vitro. Conditional deletion of the Egfr gene from podocytes of mice alleviates crescentic glomerulonephritis and the clinical features that accompany RPGN. Finally, pharmacological blockade of EGFR also prevents nephrotic syndrome, infiltration of T cells and macrophages, necrotizing crescentic glomerulonephritis, acute renal failure and death in mice. This approach is effective even when started 4 days after the induction of experimental RPGN, suggesting that targeting the HB-EGF/EGFR pathway could also be clinically beneficial for treatment of human RPGN.
Mick Kulikowski | EurekAlert!
Penn vet research identifies new target for taming Ebola
12.01.2017 | University of Pennsylvania
The strange double life of Dab2
10.01.2017 | University of Miami Miller School of Medicine
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration
"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...
Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.
Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
16.01.2017 | Power and Electrical Engineering
16.01.2017 | Information Technology
16.01.2017 | Power and Electrical Engineering