Mount Sinai Study Points to New Biological Mechanisms, Treatment Paradigm for Kidney Disease
Drug research and development should target cell-cell interactions that promote disease progression.
Prevention and reversal of chronic kidney disease is an urgent public health need. The disease affects 1 in 10 Americans, is debilitating and deadly, and existing drugs, at best, offer only mild delay in progression to end-stage kidney failure. New research led by Icahn School of Medicine at Mount Sinai investigators has uncovered abnormal molecular signaling pathways from disease initiation to irreversible kidney damage, kidney failure, and death. Results from their preclinical and human research are published online March 3 in the Journal of Clinical Investigation.
"Our group is the first to show that endothelial mitochondrial oxidative stress [damage to blood vessel lining that affects the energy-producing part of the cell caused by oxidative stress] regulates the passage of proteins from blood to urine and filtration of waste products in the kidney," said Erwin Bottinger, MD, Director of the Charles Bronfman Institute for Personalized Medicine, and the study’s senior author. Specifically, the researchers found albuminuria (protein in the urine) and depletion of the cells that form the kidney’s glomerular filtration barrier. "These findings were unexpected and open the door for developing new therapeutic targets," Dr. Bottinger added.
In the preclinical part of the research, investigators used a mouse model to induce scarring in the filtration part of the kidney, or glomeruli. This allowed progressive amounts of protein to pass into the urine and interfered with the clearance of waste products by the kidney. Essentially, the researchers were examining how different signaling mechanism and cellular interactions work, and how when they are disturbed, they promote chronic kidney disease.
Initially, key cells of the glomerular filtration barrier, also called podocytes, cause alterations in endothelin-1, a vasoconstrictor, activating the endothelin receptor A. The activated endothelin receptor A triggered disturbances manifested as endothelial mitochondrial oxidative stress.
The research team was able to confirm that this worked the same way in humans. They studied kidney biopsies, comparing ten biopsies with glomerular sclerosis with six controls. Like in the animal models, the researchers confirmed activated endothelin receptor A and endothelial mitochondrial dysfunction in human glomerular sclerosis biopsies, but not in controls.
"These processes were absolutely essential in causing protein in the urine [or albuminuria], injured podocytes (tiny ball-shaped structures that constrict the blood vessels in the filtering part of the kidney), and cause scarring, all of which can ultimately lead to long-term, irreversible kidney disease. "This is called crosstalk and it is poorly understood," said Ilse S. Daehn, PhD, the study’s lead researcher, and Assistant Professor of Medicine in the Division of Nephrology, at the Icahn School of Medicine at Mount Sinai. "We hope that these novel crosstalk findings lead to new therapies that help reverse or arrest chronic kidney disease, which affect millions of Americans," added Dr. Daehn.
Antioxidants that target the mitochondria and endothelin antagonists would alter the paradigm for preventing cell depletion and scarring of the filtration part of the kidney. "There is a pressing unmet medical need to prevent or reverse chronic kidney disease," Dr. Bottinger stressed. "The renin angiotensin inhibitors and angiotensin receptor blockers that are now widely used have not been proven effective in preventing end stage kidney failure. We need more effective drugs to treat the millions of Americans suffering from chronic kidney disease with the goal to eliminate its progression to end- stage kidney failure and with it the need for chronic dialysis and kidney transplantation."
Other investigators from the Icahn School of Medicine at Mount Sinai also contributed to this research. In addition, investigators from Columbia University, the University of Heidelberg, and University of Gothenburg contributed to this research.
The work was funded by research grants 5U01DK060995, 5R01DK056077, 5R01DK060043, and 1R01DK097253-01A1 awarded by the National Institute for Diabetes and Digestive and Kidney Diseases to Dr. Bottinger.
About the Mount Sinai Health System
The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven member hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services—from community-based facilities to tertiary and quaternary care.
The System includes approximately 6,600 primary and specialty care physicians, 12-minority-owned free-standing ambulatory surgery centers, over 45 ambulatory practices throughout the five boroughs of New York City, Westchester, and Long Island, as well as 31 affiliated community health centers. Physicians are affiliated with the Icahn School of Medicine at Mount Sinai, which is ranked among the top 20 medical schools both in National Institutes of Health funding and by U.S. News & World Report.