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Receptor protein appears to be key in breakdown of kidney filtration
Date:12/19/2007

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.

Reisers 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 receptors 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
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Contact: Sue McGreevey
smcgreevey@partners.org
617-724-2764
Massachusetts General Hospital
Source:Eurekalert

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