“Proteinuria affects hundreds of millions of people around the world and is a significant risk factor for kidney failure and cardiovascular complications,” says Jochen Reiser, MD, PhD, director of the Program in Glomerular Disease at the MGH Renal Division, one of the study’s senior authors. “Our report is the first to describe a mechanism for non-inherited proteinuria and suggests a possible therapy directed against that mechanism.” The study was an equal collaboration between two independent MGH-Renal research teams, the other led by co-senior author Sanja Sever, PhD.

The kidney’s filtering activity takes place in clusters of blood vessels called glomeruli. Within those structures, extensions from cells called podocytes wrap around blood vessels. Tiny slits in the podocytes filter out excess water and waste materials, keeping larger proteins and blood cells inside the vessels. In several types of kidney disease, podocytes shrink and lose their structure, which enlarges the filtering slits, allowing protein molecules into the urine.

The current study was designed to investigate the role of cathepsin L (CatL), an enzyme that normally breaks down proteins in cellular structures called lysosomes and that earlier reports suggested may be involved in proteinuria. The researchers first analyzed glomeruli from patients with several forms of kidney disease and found that CatL levels were two or more times higher than in individuals without kidney disease. Animal studies showed that a proteinuria-inducing treatment increased the activity of CatL not only in the lysosomes but also in the cytoplasm of podocytes and caused structural breakdown of the filtering extensions, a result not seen in mice totally lacking the gene for CatL.

A search for CatL’s target protein in proteinuria led to dynamin, an enzyme that many types of cells use in bringing receptors and other proteins from the external membrane into the cytoplasm. The researchers found evidence that dynamin is present in the podocytes of normal mice but reduced after the proteinuria-inducing treatment. That reduction was not seen in the CatL-knockout mice, suggesting that CatL was targeting dynamin. Further in vivo and in vitro experiments confirmed that CatL will split apart common forms of dynamin and identified several altered forms of dynamin that appear to be protected against CatL activity.

“Injections of two specific dynamin mutations into mice treated to induce large-scale proteinuria produced a striking effect – protein in the urine almost completely disappeared,” says Sever. “To our knowledge, this is the first successful attempt to improve kidney structure and function directly and suggests a potential therapy for proteinuria associated with several disorders.” Reiser and Sever are both assistant professors of Medicine at Harvard Medical School.

Further studies from the MGH group will focus on exactly how the altered forms of dynamin rescue podocyte function and on ways to translate these findings, for which a patent has been issued, into a treatment suitable for human patients. The study was supported by grants from the American Society for Nephrology, the National Institutes of Health, and the KMD Foundation.

Additional co-authors are Mehmet Altintas, PhD, Sharif Nankoe, Clemens Möller, David Ko, Chang-Li Wei, MD, PhD, Elizabetta del Re, and Boris Nikolic, MD, PhD, from MGH-Nephrology; Joel Henderson, MD, PhD, Brigham and Women’s Hospital; Lianne Hsing and Alexander Rudensky, PhD, Howard Hughes Medical Institute and University of Washington; Ann Erickson, PhD, University of North Carolina; Clemens Cohen, MD, University of Munich; Matthias Kretzler, MD, University of Michigan, and Dontscho Kerjaschki, MD, Vienna Medical University.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of Partners HealthCare HealthCare System, a Boston-based integrated health care delivery system.