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Receptor protein appears to be key
in breakdown of kidney filtration
Pathway may be new target
for cell-specific treatment of chronic kidney diseases
BOSTON - December
19, 2007 - Massachusetts General Hospital
(MGH) researchers have identified a new molecular pathway that appears
to be involved in urinary protein loss (proteinuria). This early-stage
kidney disease affects 100 million people around the world and is
caused by a breakdown in the kidney's filtering structures. Blocking
this pathway could be a treatment for the condition and might significantly
slow the process of kidney failure. The research team's findings
will appear in Nature Medicine and have been released online.
"We've identified a mechanism that underlies common forms
of urinary protein loss and have data showing that it is operative
in humans and in animal models of proteinuria," says Jochen
Reiser, MD, PhD, director of the Program in Glomerular Disease at
the MGH
Renal Division, the study's senior author.
"Targeting this mechanism with antibodies or small molecule
compounds can prevent or decrease proteinuria in animals, which
may represent a novel therapy for kidney diseases such as diabetic
nephropathy and focal segmental glomerulosclerosis," adds Changli
Wei, MD, PhD, first author of the article.
The kidney's filtering activity takes place in clusters of blood
vessels called glomeruli. Within those structures, extensions from
cells called podocytes wrap around blood vessels. Tiny slits in
the podocytes filter out excess water and waste materials, keeping
larger proteins and blood cells inside the vessels. In several types
of kidney disease, podocytes shrink and lose their structure, which
compromises the filtering slits, allowing protein molecules to leak
into the urine.
In the current study, the authors establish for the first time that
the podocyte extensions called foot processes are capable of motion.
In some kidney disorders, excess motility of these structures may
be involved in the breakdown of podocytes that leads to proteinuria.
To investigate this possibility, the researchers focused their attention
on molecules known to be associated with cellular motility in a
number of situations. One of these is the urokinase receptor (uPAR),
which is known to be involved in wound healing and inflammation,
as well as tumor invasion and metastasis.
Reiser's team found that uPAR expression is elevated in glomerular
cells of patients with several forms of kidney disease, compared
with healthy controls. Animal studies showed that uPAR is expressed
in all glomerular cells, yet it does not appear to be required for
normal kidney function, since renal function is not compromised
in mice lacking the gene for the protein. When the uPAR-knockout
mice were treated with a substance that usually induces proteinuria,
they did not develop the condition, suggesting that the receptor's
presence is required for the breakdown of podocyte structure.
After the gene encoding uPAR was introduced into podocytes of the
knockout mice, they began expressing the receptor within 24 hours
and became susceptible to the proteinuria-inducing treatment. The
researchers then showed that uPAR can associate with and activate
another receptor protein, alphavbeta3 integrin, leading to podocyte
motility. Blocking this step in the uPAR-controlled pathway could
reduce or prevent the development of proteinuria in mice. Such an
agent is currently in phase II clinical trials for the brain tumor
glioblastoma and may become available for use in patients with proteinuria.
Further investigation is required to discover how the uPAR pathway
may interact with other molecular mechanisms involved in proteinuria,
including the activity of an enzyme called cathepsin L, reported
earlier this year by members of the same research team. "We
are working now in two directions - to better understand the relationship
between uPAR and cathepsin L and to conduct a clinical trial with
small molecules blocking uPAR or alphavbeta3 integrin," says
Reiser, an assistant professor of Medicine at Harvard Medical School.
"We hope this could be the first step towards a cell-specific
treatment of proteinuric kidney diseases that would add on to the
great success of standard, but non-cell-specific interventions for
these diseases."
The study was supported by grants from the KMD Foundation, the American
Society for Nephrology, the National Institutes of Health, and the
George M. O'Brien Kidney Center. A patent application for the study's
findings has been filed. Additional co-authors of the Nature Medicine
report are Clemens Möller, Mehmet Altintas, Jing Li, Vineet
Gupta and Boris Nikolic of the MGH Renal Division; Karin Schwarz,
Homburg University; Serena Zacchigna and Peter Carmeliet, Catholic
University of Leuven, Belgium; Liang Xie and Raghu Kalluri, Beth
Israel Deaconess Medical Center; Anna Henger and Matthias Kretzler,
University of Michigan; Holger Schmid, University of Munich; Maria
Rastaldi, San Carlo Borromeo Hospital, Milan; Peter Cowan, St. Vincent's
Hospital Melbourne; Roberto Parrilla, Centre of Biological Research,
Madrid; Moïse Bendayan, University of Montreal; and Peter Mundel,
Mount Sinai School of Medicine, New York.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $500 million
and major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, systems biology, transplantation biology and photomedicine.
Media Contacts: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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