Penn researchers discover cause of kidney failure in diabetic mice

June 29, 2000

Targeted drug treatments to prevent renal failure in diabetics can now be developed

(Philadelphia, PA) -- 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 Fuad Ziyadeh, MD, principal investigator of the study and professor of medicine at Penn. "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." 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 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 Ziyadeh, a member of the Renal-Electrolyte and Hypertension Division in the Hospital of the University of Pennsylvania (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."
-end-
Ziyadeh's principal colleague in the research was Kumar Sharma, MD, of Thomas Jefferson University. Other investigators involved in the study were Brenda B. Hoffman, MD; Dong Cheol Han, MD, PhD; 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.

Editor's note: Fuad Ziyadeh, MD, can be reached by calling Sue Montgomery in the Public Affairs office at 215-349-5657 or 215-662-2560.




University of Pennsylvania School of Medicine

Related Diabetes Articles from Brightsurf:

New diabetes medication reduced heart event risk in those with diabetes and kidney disease
Sotagliflozin - a type of medication known as an SGLT2 inhibitor primarily prescribed for Type 2 diabetes - reduces the risk of adverse cardiovascular events for patients with diabetes and kidney disease.

Diabetes drug boosts survival in patients with type 2 diabetes and COVID-19 pneumonia
Sitagliptin, a drug to lower blood sugar in type 2 diabetes, also improves survival in diabetic patients hospitalized with COVID-19, suggests a multicenter observational study in Italy.

Making sense of diabetes
Throughout her 38-year nursing career, Laurel Despins has progressed from a bedside nurse to a clinical nurse specialist and has worked in medical, surgical and cardiac intensive care units.

Helping teens with type 1 diabetes improve diabetes control with MyDiaText
Adolescence is a difficult period of development, made more complex for those with Type 1 diabetes mellitus (T1DM).

Diabetes-in-a-dish model uncovers new insights into the cause of type 2 diabetes
Researchers have developed a novel 'disease-in-a-dish' model to study the basic molecular factors that lead to the development of type 2 diabetes, uncovering the potential existence of major signaling defects both inside and outside of the classical insulin signaling cascade, and providing new perspectives on the mechanisms behind insulin resistance in type 2 diabetes and possibly opportunities for the development of novel therapeutics for the disease.

Tele-diabetes to manage new-onset diabetes during COVID-19 pandemic
Two new case studies highlight the use of tele-diabetes to manage new-onset type 1 diabetes in an adult and an infant during the COVID-19 pandemic.

Genetic profile may predict type 2 diabetes risk among women with gestational diabetes
Women who go on to develop type 2 diabetes after having gestational, or pregnancy-related, diabetes are more likely to have particular genetic profiles, suggests an analysis by researchers at the National Institutes of Health and other institutions.

Maternal gestational diabetes linked to diabetes in children
Children and youth of mothers who had gestational diabetes during pregnancy are at increased risk of diabetes themselves, according to new research published in CMAJ (Canadian Medical Association Journal).

Two diabetes medications don't slow progression of type 2 diabetes in youth
In youth with impaired glucose tolerance or recent-onset type 2 diabetes, neither initial treatment with long-acting insulin followed by the drug metformin, nor metformin alone preserved the body's ability to make insulin, according to results published online June 25 in Diabetes Care.

People with diabetes visit the dentist less frequently despite link between diabetes, oral health
Adults with diabetes are less likely to visit the dentist than people with prediabetes or without diabetes, finds a new study led by researchers at NYU Rory Meyers College of Nursing and East Carolina University's Brody School of Medicine.

Read More: Diabetes News and Diabetes Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.