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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 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.

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Figure 1: uPAR is induced in podocytes in proteinuric patients and experimental proteinuric models.
Figure 2: uPAR is required in podocytes for the development of foot process effacement and proteinuria.
Figure 3: uPAR-mediated podocyte motility and proteinuria involves αvβ3 integrin and vitronectin.
Figure 4: uPAR activates β3 integrin.
Figure 5: The active uPAR-αvβ3 integrin complex is lipid dependent and its blockade modifies proteinuria.

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Acknowledgements

Antibody to WOW-1 fragment (Fab) was a gift from S. Shattil (University of California, San Diego, La Jolla, California). Rabbit polyclonal antibody and NPHS2 promoter vector p2.5 cDNA were gifts from L. Holzman (University of Michigan). Vtn−/− mice were a gift from D. Ginsburg (University of Michigan) and Itgb3−/− mice were obtained from R. Kalluri (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston). PLAURD262A 37 cDNA was a gift from Y. Wei and H.A. Chapman (University of California, San Francisco). J.R. was supported by the KMD Foundation and the Kidney-Urology Foundation of America–American Society of Nephrology (KUFA-ASN) Research. This work was supported by US National Institutes of Health (NIH) grants DK073495 (to J.R.), DK057683, DK062472 and the George M. O'Brien Kidney Center DK064236 (to P.M.). C.W. is the Halpin Scholar of the American Society of Nephrology. C.C.M. was supported by a scholarship of the German Academic Exchange Service. M.M.A. was supported by NIH training grant T32DK007540. Gene expression studies of uPAR in human disease were performed in the framework of the European renal cDNA bank. We thank all members of the European Renal cDNA Bank and their patients for their support (for participating centers at the time of the study, see ref. 26). Part of the electron microscopy work was performed in the Microscopy Core facility of the Massachusetts General Hospital Program in Membrane Biology and was supported by an NIH Program Project grant (DK38452).

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Correspondence to Jochen Reiser.

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Wei, C., Möller, C., Altintas, M. et al. Modification of kidney barrier function by the urokinase receptor. Nat Med 14, 55–63 (2008). https://doi.org/10.1038/nm1696

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