Article abstract
Nature Medicine 14, 55 - 63 (2008)
Published online: 16 December 2007 | doi:10.1038/nm1696
Modification of kidney barrier function by the urokinase receptor
Changli Wei1, Clemens C Möller1, Mehmet M Altintas1, Jing Li1, Karin Schwarz2, Serena Zacchigna3,4, Liang Xie5, Anna Henger6, Holger Schmid7, Maria P Rastaldi8, Peter Cowan9, Matthias Kretzler6, Roberto Parrilla10, Moïse Bendayan11, Vineet Gupta1, Boris Nikolic1, Raghu Kalluri5, Peter Carmeliet3,4, Peter Mundel12 & Jochen Reiser1
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 
v
3 integrin. Mice lacking uPAR (Plaur-
/-
) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active 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 v3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of v3 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.
- Nephrology Division and Program in Glomerular Disease, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA.
- Institute for Anatomy and Cell Biology, Homburg University, Homburg 66421, Germany.
- The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
- Department of Transgene Technology and Gene Therapy, Vlaams Interuniversitair Instituut voor Biotechnologie, 3000 Leuven, Belgium.
- Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
- Medizinische Poliklinik, University of Munich, Munich 80336, Germany.
- Renal Immunopathology Laboratory, Associazione Nuova Nefrologia and Fondazione D'Amico per la Ricerca sulle Malattie Renali, c/o San Carlo Borromeo Hospital, Milan, 20153, Italy.
- Immunology Research Centre, St. Vincent's Hospital, Melbourne, Victoria 3065, Australia.
- Department of Pathophysiology and Human Molecular Genetics, Centro de Investigaciones Biológicas, Madrid, 28040, Spain.
- Department of Pathology, Université de Montréal, Montreal, Quebec H3T 1J4, Canada.
- Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Correspondence to: Jochen Reiser1 e-mail: jreiser@partners.org
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