NEW YORK—Kidney disease is a complication faced by a moderate percentage of diabetic individuals, with the National Kidney Foundation reporting that approximately 30 percent of patients with type 1 diabetes and 10 to 40 percent of patients with type 2 diabetes will face kidney failure in their lives. Though treatment options exist, diagnostic options for this slow-developing disease, particularly in early stages, are somewhat lacking.
However, new answers about the root of disease development, courtesy of researchers from the Icahn School of Medicine at Mount Sinai, could point to new diagnostic targets.
“Diabetic kidney disease is one of the major causes of death in diabetic patients, and is also the leading single cause of end-stage renal disease in the United States,” said Dr. Ilse S. Daehn, assistant professor of medicine (nephrology) at the Icahn School of Medicine at Mount Sinai and senior investigator on this work.
“There is a high percentage of diabetics that are susceptible to getting diabetic kidney disease, but most diabetics don't [develop it]. It is difficult to identify the patients that are at risk to getting kidney disease and other complications, from the diabetics that will not get the disease,” she adds. “That has been a huge challenge in the field—to really understand why some people develop and why some don't, also in those that develop the disease early enough, what to do to prevent further progression? Because it takes 10-15 years for disease to really develop.”
In an effort to get some answers about disease progression, Daehn, who is also a member of The Charles Bronfman Institute for Personalized Medicine, and her team turned their attention to the cellular level of things. Most of their work focused on the glomerulus, globular bodies in the kidney that are full of capillaries and other structures. These bodies are the first line of filtration and a key aspect of the body’s mechanism for filtering waste products out of blood to be expelled from the body.
For this work, the researchers looked at endothelial cells and podocytes within the glomerulus, modeling their work in two sets of mice: one that would develop diabetic kidney disease and one with natural resistance to the disease. In the disease-prone mice, endothelial cells—wafer-like cells that form the inner lining of blood vessels—had stressed mitochondria, and as such produced excess reactive oxygen species (ROS), molecules that play a role in cell signaling but that can damage DNA and cell proteins if overproduced.
When an endothelial cell faces excess amounts of ROS, podocytes begin to be destroyed. These cells surround and work with capillaries and other cell types in the glomerulus, and when they are lost, the glomerulus becomes brittle, capillaries collapse and kidneys become leaky, which leads to the loss of essential body proteins. This cascade of damage leads to kidney failure, which is what turns into end-stage kidney disease.
“For the last 20 or so years, the field has been focused on podocytes, which are specialized epithelial cells in the glomerulus. We hypothesize that there is cross-talk between cells in the glomerulus, and that there's an important cross-communication between endothelial cells and podocytes in diabetic kidney disease,” Daehn explains. “We propose that endothelial dysfunction precedes podocyte abnormalities, and therefore studying endothelial dysfunction we could get novel insights in kidney disease development. In the past people have overlooked the endothelial compartment of the glomerulus, we are specifically exploring an area where not many people have, our field is evolving quickly, so these are very exciting times.”
A search for upstream mechanisms for regulating mitochondrial stress in the glomerulus’ endothelium revealed a pathway for managing oxidative stress, one that produced excess quantities of the cell receptor endothelium receptor-A and its ligand. The team then took a look at urine and kidney biopsies from diabetic kidney disease patients and saw similar results: molecules linked to oxidative stress and disease progression were found in the urine, and the biopsies revealed increases in mitochondrial DNA damage and endothelium receptor-A expression. When they administered BQ-123, an experimental small molecule, to block endothelium receptor-A in mouse models, the disease-prone mice did not develop diabetic kidney disease.
In their work, Daehn and her colleagues found that in disease-prone mice, they could measure molecules linked to excess ROS. Daehn noted that this could make it possible both to develop a biomarker to alert physicians of early disease development and to offer another therapeutic approach in the collection of ROS molecules.
“One of the next steps would be to identify key biomarkers that can differentiate individuals that will develop diabetic kidney disease from the ones that won't, and endothelial injury would be interesting to consider, because our study shows that endothelial mitochondrial oxidative stress in the glomerulus is the key differentiator between the susceptible mouse strains and the resistant mouse strains,” Daehn tells DDNews. “So we are currently investigating early endothelial changes in susceptible individuals in addition to understanding the mechanisms and the genetics behind susceptibility.”