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Molecular mechanism of common forms
of kidney disease identified
Enzyme causes protein to leak from
blood into urine, changes to target may restore kidney function
BOSTON - August 1, 2007 - Massachusetts General Hospital
(MGH) researchers have identified a key mechanism underlying proteinuria
- excess protein in the urine which signifies a breakdown in the
kidney's filtering process. They have discovered that a protein
called dynamin is required for the function of a critical filtering
structure called a podocyte and that a specific enzyme's processing
of dynamin will cause podocytes to break down, allowing protein
to leak out of the bloodstream. In their report in the August Journal
of Clinical Investigation, the researchers also describe how
altered forms of dynamin may be able to block the process and restore
kidney function.
"Proteinuria affects hundreds of millions of people around
the world and is a significant risk factor for kidney failure and
cardiovascular complications," says Jochen Reiser, MD, PhD,
director of the Program in Glomerular Disease at the MGH
Renal Division, one of the study's senior authors. "Our
report is the first to describe a mechanism for non-inherited proteinuria
and suggests a possible therapy directed against that mechanism."
The study was an equal collaboration between two independent MGH-Renal
research teams, the other led by co-senior author Sanja Sever, PhD.
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
enlarges the filtering slits, allowing protein molecules into the
urine.
The current study was designed to investigate the role of cathepsin
L (CatL), an enzyme that normally breaks down proteins in cellular
structures called lysosomes and that earlier reports suggested may
be involved in proteinuria. The researchers first analyzed glomeruli
from patients with several forms of kidney disease and found that
CatL levels were two or more times higher than in individuals without
kidney disease. Animal studies showed that a proteinuria-inducing
treatment increased the activity of CatL not only in the lysosomes
but also in the cytoplasm of podocytes and caused structural breakdown
of the filtering extensions, a result not seen in mice totally lacking
the gene for CatL.
A search for CatL's target protein in proteinuria led to dynamin,
an enzyme that many types of cells use in bringing receptors and
other proteins from the external membrane into the cytoplasm. The
researchers found evidence that dynamin is present in the podocytes
of normal mice but reduced after the proteinuria-inducing treatment.
That reduction was not seen in the CatL-knockout mice, suggesting
that CatL was targeting dynamin. Further in vivo and in vitro experiments
confirmed that CatL will split apart common forms of dynamin and
identified several altered forms of dynamin that appear to be protected
against CatL activity.
"Injections of two specific dynamin mutations into mice treated
to induce large-scale proteinuria produced a striking effect - protein
in the urine almost completely disappeared," says Sever. "To
our knowledge, this is the first successful attempt to improve kidney
structure and function directly and suggests a potential therapy
for proteinuria associated with several disorders." Reiser
and Sever are both assistant professors of Medicine at Harvard Medical
School.
Further studies from the MGH group will focus on exactly how the
altered forms of dynamin rescue podocyte function and on ways to
translate these findings, for which a patent has been issued, into
a treatment suitable for human patients. The study was supported
by grants from the American Society for Nephrology, the National
Institutes of Health, and the KMD Foundation.
Additional co-authors are Mehmet Altintas, PhD, Sharif Nankoe,
Clemens Möller, David Ko, Chang-Li Wei, MD, PhD, Elizabetta
del Re, and Boris Nikolic, MD, PhD, from MGH-Nephrology; Joel Henderson,
MD, PhD, Brigham and Women's Hospital; Lianne Hsing and Alexander
Rudensky, PhD, Howard Hughes Medical Institute and University of
Washington; Ann Erickson, PhD, University of North Carolina; Clemens
Cohen, MD, University of Munich; Matthias Kretzler, MD, University
of Michigan, and Dontscho Kerjaschki, MD, Vienna Medical University.
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 nearly $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.
MGH and Brigham and Women's Hospital are founding members of Partners
HealthCare HealthCare System, a Boston-based integrated health care
delivery system.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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