Modification of kidney barrier function by the urokinase receptor

Changli Wei, Clemens C. Möller, Mehmet M. Altintas, Jing Li, Karin Schwarz, Serena Zacchigna, Liang Xie, Anna Henger, Holger Schmid, Maria P. Rastaldi, Peter Cowan, Matthias Kretzler, Roberto Parrilla, Moïse Bendayan, Vineet Gupta, Boris Nikolic, Raghu Kalluri, Peter Carmeliet, Peter Mundel, Jochen Reiser

Research output: Contribution to journalArticlepeer-review

464 Scopus citations


Podocyte dysfunction, represented by foot process effacement and proteinuria, is often the starting point for progressive kidney disease. Therapies aimed at the cellular level of the disease are currently not available. Here we show that induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via a mechanism that includes lipid-dependent activation of αvβ3 integrin. Mice lacking uPAR (Plaur-/-) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active β3 integrin. Gene transfer studies reveal a prerequisite for uPAR expression in podocytes, but not in endothelial cells, for the development of LPS-mediated proteinuria. Mechanistically, uPAR is required to activate αvβ3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of αvβ3 integrin reduces podocyte motility in vitro and lowers proteinuria in mice. Our findings show a physiological role for uPAR signaling in the regulation of kidney permeability.

Original languageEnglish (US)
Pages (from-to)55-63
Number of pages9
JournalNature Medicine
Issue number1
StatePublished - Jan 2008
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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