Featured Research

from universities, journals, and other organizations

Receptor Protein Appears To Be Key In Breakdown Of Kidney Filtration

Date:
December 25, 2007
Source:
Massachusetts General Hospital
Summary:
Researchers have identified a new molecular pathway that appears to be involved in urinary protein loss, an early-stage kidney disease that affects 100 million people around the world, and is caused by a breakdown in the kidney's filtering structures. The pathway may be new target for cell-specific treatment of chronic kidney diseases.

Massachusetts General Hospital (MGH) researchers have identified a new molecular pathway that appears to be involved in urinary protein loss (proteinuria). This early-stage kidney disease affects 100 million people around the world and is caused by a breakdown in the kidney's filtering structures. Blocking this pathway could be a treatment for the condition and might significantly slow the process of kidney failure. 

"We've identified a mechanism that underlies common forms of urinary protein loss and have data showing that it is operative in humans and in animal models of proteinuria," says Jochen Reiser, MD, PhD, director of the Program in Glomerular Disease at the MGH Renal Division, the study's senior author.

"Targeting this mechanism with antibodies or small molecule compounds can prevent or decrease proteinuria in animals, which may represent a novel therapy for kidney diseases such as diabetic nephropathy and focal segmental glomerulosclerosis," adds Changli Wei, MD, PhD, first author of the article.

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 research team's findings will appear in Nature Medicine and have been released online.

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 Mφller, 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; Moοse Bendayan, University of Montreal; and Peter Mundel, Mount Sinai School of Medicine, New York.


Story Source:

The above story is based on materials provided by Massachusetts General Hospital. Note: Materials may be edited for content and length.


Cite This Page:

Massachusetts General Hospital. "Receptor Protein Appears To Be Key In Breakdown Of Kidney Filtration." ScienceDaily. ScienceDaily, 25 December 2007. <www.sciencedaily.com/releases/2007/12/071219154011.htm>.
Massachusetts General Hospital. (2007, December 25). Receptor Protein Appears To Be Key In Breakdown Of Kidney Filtration. ScienceDaily. Retrieved August 22, 2014 from www.sciencedaily.com/releases/2007/12/071219154011.htm
Massachusetts General Hospital. "Receptor Protein Appears To Be Key In Breakdown Of Kidney Filtration." ScienceDaily. www.sciencedaily.com/releases/2007/12/071219154011.htm (accessed August 22, 2014).

Share This




More Health & Medicine News

Friday, August 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Drug Used To Treat 'Ebola's Cousin' Shows Promise

Drug Used To Treat 'Ebola's Cousin' Shows Promise

Newsy (Aug. 21, 2014) — An experimental drug used to treat Marburg virus in rhesus monkeys could give new insight into a similar treatment for Ebola. Video provided by Newsy
Powered by NewsLook.com
Two US Ebola Patients Leave Hospital Free of the Disease

Two US Ebola Patients Leave Hospital Free of the Disease

AFP (Aug. 21, 2014) — Two American missionaries who were sickened with Ebola while working in Liberia and were treated with an experimental drug are doing better and have left the hospital, doctors say on August 21, 2014. Duration: 01:05 Video provided by AFP
Powered by NewsLook.com
Cadavers, a Teen, and a Medical School Dream

Cadavers, a Teen, and a Medical School Dream

AP (Aug. 21, 2014) — Contains graphic content. He's only 17. But Johntrell Bowles has wanted to be a doctor from a young age, despite the odds against him. He was recently the youngest participant in a cadaver program at the Indiana University NW medical school. (Aug. 21) Video provided by AP
Powered by NewsLook.com
American Ebola Patients Released: What Cured Them?

American Ebola Patients Released: What Cured Them?

Newsy (Aug. 21, 2014) — It's unclear whether the American Ebola patients' recoveries can be attributed to an experimental drug or early detection and good medical care. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins