Penn Researchers Discover Cause of Kidney Failure
in Diabetic Mice
Targeted Drug Treatments to Prevent Renal Failure in
Diabetics Can Now Be Developed
Researchers at the University of Pennsylvania School of Medicine have
demonstrated in an animal model that diabetic kidney failure is triggered
by a protein that can be neutralized, thus effectively blocking the development
of kidney disease--which is one of the most deadly side-effects of diabetes.
The scientists' work demonstrates that renal failure in mice is caused directly
by the transforming growth factor-beta (TGF-beta) protein--which stimulates
the development of sclerosis, or scar tissue, inside the kidneys and which
eventually prohibits the organs from effectively filtering toxins.
To test their hypothesis that diabetic kidney disease in the mouse was
due to the over-production of TGF-beta, the researchers administered a selective
antibody that antagonized, or neutralized, the activity of the growth factor.
"What we found is that sclerosis was prevented," reports nephrologist
Dr. Fuad Ziyadeh, principal investigator of the study and professor of medicine.
"To our knowledge, this is the first proof-of-concept study to establish
that kidney disease in diabetes is caused by this growth-factor protein."
Dr. Ziyadeh suggests that pharmaceutical companies may now seek to develop
drugs that would inhibit the metabolic actions of the TGF-beta protein in
the kidney. The new finding--which appears in the July 5 issue of Proceedings
of the National Academy of Science --grew from earlier work done by
Dr. Ziyadeh and his team of investigators. Indeed, they had demonstrated
previously that the ill effects of high levels of glucose in the kidney
cells of diabetic mice were caused by excess transforming growth factor-beta,
and that the onset of kidney disease in mice was prevented when that growth
protein was neutralized.
The current research addresses both juvenile and adult-onset (or Type
II) diabetes explains Dr. Ziyadeh, a member of the Renal-Electrolyte and
Hypertension Division in HUP. The latter type is increasing in the developed
world as the population ages and obesity becomes more common. The disease
leaves the body unable to produce enough insulin to dispose of glucose in
its cells, or causes the body's cells to resist the action of insulin. Despite
recent progress in treating hyperglycemia and hypertension in patients with
diabetes, little progress has been made in curing or preventing renal failure,
which eventually afflicts about 30 percent of those who suffer from diabetes.
In fact, diabetes causes about 40 percent of all kidney failures in the
United States, and is the number-one cause of kidney failure in the industrialized
world. At present, the only treatment alternatives available are dialysis
or transplant surgery. Despite these treatments, the mortality rate remains
20 percent per year, which Ziyadeh says is similar to the death rate of
major cancers. The research was conducted on a strain of mice that develops
Type II diabetes, spontaneously, and it compared the kidneys of non-diabetic
mice and diabetic mice from the same litter. The study commenced when the
mice were eight weeks old because, by that time, hyperglycemia was evident
in all the diabetic mice. For the next eight weeks, one group of diabetic
mice and one group of non-diabetic mice were injected three times weekly
with a murine monoclonal antibody that can neutralize any of the three forms
of TGF-beta that are found in mammals. As a control, a second group of diabetic
and non-diabetic mice received an irrelevant antibody. The diabetic mice
remained hyperglycemic throughout the experiment. Neutralizing all three
forms of TGF-beta with the antibody resulted in marked beneficial effects
on both renal function and structure, according to the study's findings.
Kidney filtration capacity was preserved and sclerosis did not develop in
the diabetic mice receiving the antibody. Further, the researchers concluded
that their results "strongly suggest that chronic nephropathy in the
diabetic mice was prevented." Dr. Ziyadeh's principal colleague in
the research was Dr. Kumar Sharma, of Thomas Jefferson University. Other
investigators involved in the study were Dr. Brenda B. Hoffman; Dr. Dong
Cheol Han; Dr. M. Carmen Iglesias-de la Cruz, PhD; Soon Won Hong, MD; Motohide
Isono, MD, PhD; Sheldon Chen, MD; and Tracey A. McGowan, MD.
The research was funded in part by the Juvenile Diabetes Foundation International,
the National Institutes of Health, and the National Kidney Foundation.