Modification of kidney barrier function by the urokinase receptor

被引：446

作者：

Wei, Changli ^{[1
,2
]}

Moeller, Clemens C. ^{[1
,2
]}

Altintas, Mehmet M. ^{[1
,2
]}

Li, Jing ^{[1
,2
]}

Schwarz, Karin

Zacchigna, Serena ^{[3
,4
]}

Xie, Liang ^{[5
]}

Henger, Anna ^{[6
]}

Schmid, Holger ^{[7
]}

Rastaldi, Maria P. ^{[8
]}

Cowan, Peter ^{[9
]}

Kretzler, Matthias ^{[6
]}

Parrilla, Roberto ^{[10
]}

Bendayan, Se ^{[11
]}

Gupta, Vineet ^{[1
,2
]}

Nikolic, Boris ^{[1
,2
]}

Kalluri, Raghu ^{[5
]}

Carmeliet, Peter ^{[3
,4
]}

Mundel, Peter ^{[12
]}

Reiser, Jochen ^{[1
,2
]}

机构：

[1] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Nephrol Div, Boston, MA 02129 USA

[2] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Program Glamerular Dis, Boston, MA 02129 USA

[3] Katholieke Univ Leuven, Flanders Interuniv Inst Biotechnol, Ctr Transgene Technol & Gene Therapy, B-3000 Louvain, Belgium

[4] Vlaans Interuniv Inst Biotechnol, Dept Transgene Technol & Gene Therapy, B-3000 Louvain, Belgium

[5] Beth Israel Deaconess Med Ctr, Dept Med, Div Matrix Biol, Boston, MA 02215 USA

[6] Univ Michigan Hosp, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA

[7] Univ Munich, Med Poliklin, D-80336 Munich, Germany

[8] San Carlo Borromeo Hosp, Assoc Nuova Nefrol & Fdn Damico Ricerca Malattie, Renal Immunopathol Lab, I-20153 Milan, Italy

[9] St Vincents Hosp, Immunol Res Ctr, Fitzroy, Vic 3065, Australia

[10] CSIC, Ctr Invest Biol, Dept Pathophysiol & Human Mol Genet, Madrid 28040, Spain

[11] Univ Montreal, Dept Pathol, Montreal, PQ H3T 1J4, Canada

[12] Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA

来源：

NATURE MEDICINE | 2008年 / 14卷 / 01期

关键词：

D O I：

10.1038/nm1696

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 alpha v beta 3 integrin. Mice lacking uPAR (Plaur(-/-)) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active beta 3 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 alpha v beta 3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of alpha v beta 3 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.

引用

页码：55 / 63

页数：9

共 51 条

[1] Urokinase-urokinase receptor interaction mediates an inhibitory signal for HIV-1 replication [J].