title: Modification of kidney barrier function by the urokinase receptor.
abstract: 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 alphavbeta3 integrin. Mice lacking uPAR (Plaur-/-) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active beta3 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 alphavbeta3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of alphavbeta3 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.
authors: Nephrology Division and Program in Glomerular Disease, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA.
authors: Changli
authors: C
authors: Wei
authors: Clemens C
authors: CC
authors: Möller
authors: Mehmet M
authors: MM
authors: Altintas
authors: Jing
authors: J
authors: Li
authors: Karin
authors: K
authors: Schwarz
authors: Serena
authors: S
authors: Zacchigna
authors: Liang
authors: L
authors: Xie
authors: Anna
authors: A
authors: Henger
authors: Holger
authors: H
authors: Schmid
authors: Maria P
authors: MP
authors: Rastaldi
authors: Peter
authors: P
authors: Cowan
authors: Matthias
authors: M
authors: Kretzler
authors: Roberto
authors: R
authors: Parrilla
authors: Moïse
authors: M
authors: Bendayan
authors: Vineet
authors: V
authors: Gupta
authors: Boris
authors: B
authors: Nikolic
authors: Raghu
authors: R
authors: Kalluri
authors: Peter
authors: P
authors: Carmeliet
authors: Peter
authors: P
authors: Mundel
authors: Jochen
authors: J
authors: Reiser
mesh_terms: D000818:Animals; D002465:Cell Movement; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000378:metabolism; D021962:Membrane Microdomains; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D050199:Podocytes / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D015398:Signal Transduction
chemical_list: D039302:Integrin alphaVbeta3; D008070:Lipopolysaccharides; C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator