Jefferson Scientists Uncover Potential Trigger of Diabetic Kidney Disease
Scientists at Jefferson Medical College and Mount Sinai School of Medicine have identified a protein that plays a leading part in triggering kidney disease in diabetic patients, a condition known as diabetic nephropathy and the leading cause of kidney failure worldwide. The finding, which they report February 22 in the journal PLoS Medicine, could lead to the eventual development of compounds that might be used to treat diabetic kidney disease.
According to study co-author Kumar Sharma, M.D., director of the Center for Diabetic Kidney Disease at Thomas Jefferson University in Philadelphia and professor of medicine at Jefferson Medical College of Thomas Jefferson University, more than 40 percent of patients with end-stage chronic kidney disease also have diabetic nephropathy. While diabetic nephropathy affects approximately one in three people with type 1 and type 2 diabetes, how diabetes damages the kidneys is poorly understood.
Dr. Sharma, along with Erwin Böttinger, M.D., professor of medicine and pharmacology and biological chemistry at Mount Sinai School of Medicine in New York, and their co-workers looked at kidney samples from mice and people with and without diabetes and looked at the effects of high glucose on the kidney cells.
The researchers found that a protein called CD36 was present in a specific cell type called the proximal tubular epithelial cell in human diabetic kidney disease. In humans, the cells seem to be involved in a self-directed cell death or apoptosis in diabetic kidney disease. “We think CD36 might be a switch that is turned on in the human condition, and might be one of the reasons these cells die in human disease and start a cascade of progressive kidney failure,” Dr. Sharma explains. “If we can develop compounds to block CD36, it could potentially be a clinical intervention.
“Our thinking is completely novel – that CD36 is a key player in causing progressive diabetic kidney disease,” he says. “We think as the diabetic kidney gets damaged, more and more of these proteins and free fatty acids go through the urine and hit these tubular cells. The tubular cells, via CD36, take them up and start the apoptosis pathway and ultimately cause fibrosis and progressive kidney failure as a result. We found almost all of the apoptotic cells had CD36 in them. If we block CD36 in cell culture, these proteins and free fatty acids don’t cause apoptosis.”
Next, the researchers would like to develop a mouse model that overexpresses CD36. “By increasing CD36 levels, we’d like to find out if this does cause the apoptotic pathway with co-existing diabetes,” Dr. Sharma says. He notes that there is some evidence showing that CD36 might be involved in vascular damage in diabetes and lead to atherosclerosis. It might play an important role not only in the kidney but in the vasculature and in the development of atherosclerosis.
Dr. Sharma currently is conducting a study to evaluate how a new medicine may reduce scar tissue in damaged kidneys. “The goal of this study – the only one of its kind in the United States – is to evaluate the extent to which a new compound, called pirfenidone, can prevent the kidney scarring that often results from diabetes,” he says.
Kidney scarring results from the excessive activity of a molecule called transforming growth factor-beta (TGF-beta). In previous studies, Dr. Sharma’s research group found the TGF-beta stimulates overproduction of the scar tissue in the kidneys of diabetic patients and prevents normal kidney function. The new drug, pirfenidone, was shown to block the damaging effects of TGF-beta. “This trial will help us is to see if an antifibrotic approach will add to the armamentarium of arresting diabetic nephropathy.”
Steve Benowitz | EurekAlert!
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