Modification of kidney barrier function by the urokinase receptor.
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.
Wei
Changli
C
Nephrology Division and Program in Glomerular Disease, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA.
Möller
Clemens C
CC
Altintas
Mehmet M
MM
Li
Jing
J
Schwarz
Karin
K
Zacchigna
Serena
S
Xie
Liang
L
Henger
Anna
A
Schmid
Holger
H
Rastaldi
Maria P
MP
Cowan
Peter
P
Kretzler
Matthias
M
Parrilla
Roberto
R
Bendayan
Moïse
M
Gupta
Vineet
V
Nikolic
Boris
B
Kalluri
Raghu
R
Carmeliet
Peter
P
Mundel
Peter
P
Reiser
Jochen
J
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
D039302:Integrin alphaVbeta3; D008070:Lipopolysaccharides; C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator