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.

Almanac, Vol. 47, No. 1, July 18, 2000