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 compromises the filtering slits, allowing protein molecules to leak into the urine.

In the current study, the authors establish for the first time that the podocyte extensions called foot processes are capable of motion. In some kidney disorders, excess motility of these structures may be involved in the breakdown of podocytes that leads to proteinuria. To investigate this possibility, the researchers focused their attention on molecules known to be associated with cellular motility in a number of situations. One of these is the urokinase receptor (uPAR), which is known to be involved in wound healing and inflammation, as well as tumor invasion and metastasis.

Reiser’s team found that uPAR expression is elevated in glomerular cells of patients with several forms of kidney disease, compared with healthy controls. Animal studies showed that uPAR is expressed in all glomerular cells, yet it does not appear to be required for normal kidney function, since renal function is not compromised in mice lacking the gene for the protein. When the uPAR-knockout mice were treated with a substance that usually induces proteinuria, they did not develop the condition, suggesting that the receptor’s presence is required for the breakdown of podocyte structure.

After the gene encoding uPAR was introduced into podocytes of the knockout mice, they began expressing the receptor within 24 hours and became susceptible to the proteinuria-inducing treatment. The researchers then showed that uPAR can associate with and activate another receptor protein, alphavbeta3 integrin, leading to podocyte motility. Blocking this step in the uPAR-controlled pathway could reduce or prevent the development of proteinuria in mice. Such an agent is currently in phase II clinical trials for the brain tumor glioblastoma and may become available for use in patients with proteinuria.

Further investigation is required to discover how the uPAR pathway may interact with other molecular mechanisms involved in proteinuria, including the activity of an enzyme called cathepsin L, reported earlier this year by members of the same research team. “We are working now in two directions – to better understand the relationship between uPAR and cathepsin L and to conduct a clinical trial with small molecules blocking uPAR or alphavbeta3 integrin,” says Reiser, an assistant professor of Medicine at Harvard Medical School. “We hope this could be the first step towards a cell-specific treatment of proteinuric kidney diseases that would add on to the great success of standard, but non-cell-specific interventions for these diseases.”

The study was supported by grants from the KMD Foundation, the American Society for Nephrology, the National Institutes of Health, and the George M. O’Brien Kidney Center. A patent application for the study’s findings has been filed. Additional co-authors of the Nature Medicine report are Clemens Möller, Mehmet Altintas, Jing Li, Vineet Gupta and Boris Nikolic of the MGH Renal Division; Karin Schwarz, Homburg University; Serena Zacchigna and Peter Carmeliet, Catholic University of Leuven, Belgium; Liang Xie and Raghu Kalluri, Beth Israel Deaconess Medical Center; Anna Henger and Matthias Kretzler, University of Michigan; Holger Schmid, University of Munich; Maria Rastaldi, San Carlo Borromeo Hospital, Milan; Peter Cowan, St. Vincent’s Hospital Melbourne; Roberto Parrilla, Centre of Biological Research, Madrid; Moïse Bendayan, University of Montreal; and Peter Mundel, Mount Sinai School of Medicine, New York.

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.