2007 JASN IMPACT FACTOR 7.111	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, G. Articles by Eddy, A. A. Search for Related Content PubMed PubMed Citation Articles by Zhang, G. Articles by Eddy, A. A.

Urokinase Receptor Modulates Cellular and Angiogenic Responses in Obstructive Nephropathy

Guoqiang Zhang^*, Heungsoo Kim^*, Xiaohe Cai^*, Jesus M. Lopez-Guisa^*, Peter Carmeliet and Allison A. Eddy^*

*University of Washington, Children’s Hospital and Regional Medical Center, Division of Nephrology, Seattle, Washington; and The Center For Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium.

Correspondence to Dr. Allison A. Eddy, Children’s Hospital and Regional Medical Center, Division of Nephrology, Mail Stop CH 5G-1, 4800 Sand Point Way NE, Seattle, WA 98105. Phone: 206-987-2524; Fax: 206-987-2636;

ABSTRACT. Interstitial cells have been implicated in the pathogenesis of renal fibrosis. Given that the urokinase receptor (uPAR) is known to play a role in cell adhesion, migration, and angiogenesis, the present study was designed to evaluate the role of uPAR in the regulation of the phenotypic composition of interstitial cells (macrophages, myofibroblasts, capillaries) in response to chronic renal injury. Groups of uPAR wild-type (+/+) and knockout (-/-) mice were investigated between 3 and 14 d after unilateral ureteral obstruction (UUO) or sham surgery (n = 8 mice per group). The density of F4/80+ interstitial macrophages (M) was significantly lower in the -/- mice (3.3 ± 0.4 versus 6.9 ± 1.7% area at day 3 UUO; 10.8 ± 1.6 versus 15.7 ± 1.0% at day 14 UUO; -/- versus +/+). In contrast, in the -/- mice there were significantly more smooth muscle actin (SMA)–positive cells (12.9 ± 3.2 versus 7.8 ± 1.5% area at day 3 UUO; 21.0 ± 4.7 versus 9.7 ± 1.9% at day 14 UUO) and CD34-positive endothelial cells (8.4 ± 1.9 versus 4.0 ± 1.1% area at day 14 UUO). These differences were associated with significantly more interstitial fibrosis in the -/- mice based on Sirius red staining (4.6 ± 0.9 versus 2.3 ± 0.9% area at 14 d UUO). Absence of the uPAR scavenger receptor was associated with significantly greater accumulation of plasminogen activator inhibitor-1 protein (PAI-1) (20.5 ± 3.5 versus 9.1 ± 2.9% area, day 14 UUO) and vitronectin protein (2.4 ± 1.1 versus 0.9 ± 0.4% area, day 14 UUO). By immunostaining SMA+ cells, CD34+ cells, vitronectin and PAI-1 co-localized to the same tubulointerstitial area. The number of apoptotic cells increased in response to UUO but was significantly higher in the -/- mice (2.0 ± 0.2 versus 1.2 ± 0.2 per 100 tubulointerstitial cells, day 14 UUO) while the number of proliferating cells was significantly lower in the uPAR-/- mice. These data suggest that uPAR deficiency suppresses renal M recruitment, but the absence of this scavenger receptor actually accentuates the fibrogenic response, likely due in part to the delayed clearance of angiogenic/profibrotic molecules such as PAI-1 and decreased receptor-associated uPA activity. E-mail: aeddy@u.washington.edu

This article has been cited by other articles:

				F. Gueler, S. Rong, M. Mengel, J.-K. Park, J. Kiyan, T. Kirsch, I. Dumler, H. Haller, and N. Shushakova Renal Urokinase-Type Plasminogen Activator (uPA) Receptor but not uPA Deficiency Strongly Attenuates Ischemia Reperfusion Injury and Acute Kidney Allograft Rejection J. Immunol., July 15, 2008; 181(2): 1179 - 1189. [Abstract] [Full Text] [PDF]

				I. Yamaguchi, J. M. Lopez-Guisa, X. Cai, S. J. Collins, D. M. Okamura, and A. A. Eddy Endogenous urokinase lacks antifibrotic activity during progressive renal injury Am J Physiol Renal Physiol, July 1, 2007; 293(1): F12 - F19. [Abstract] [Full Text] [PDF]

				G. Zhang, K. A. Kernan, S. J. Collins, X. Cai, J. M. Lopez-Guisa, J. L. Degen, Y. Shvil, and A. A. Eddy Plasmin(ogen) Promotes Renal Interstitial Fibrosis by Promoting Epithelial-to-Mesenchymal Transition: Role of Plasmin-Activated Signals J. Am. Soc. Nephrol., March 1, 2007; 18(3): 846 - 859. [Abstract] [Full Text] [PDF]

				A. Stempien-Otero, A. Plawman, J. Meznarich, T. Dyamenahalli, G. Otsuka, and D. A. Dichek Mechanisms of Cardiac Fibrosis Induced by Urokinase Plasminogen Activator J. Biol. Chem., June 2, 2006; 281(22): 15345 - 15351. [Abstract] [Full Text] [PDF]

				R. Gong, A. Rifai, E. M. Tolbert, P. Biswas, J. N. Centracchio, and L. D. Dworkin Hepatocyte Growth Factor Ameliorates Renal Interstitial Inflammation in Rat Remnant Kidney by Modulating Tubular Expression of Macrophage Chemoattractant Protein-1 and RANTES J. Am. Soc. Nephrol., November 1, 2004; 15(11): 2868 - 2881. [Abstract] [Full Text] [PDF]

				T. Wada, K. Furuichi, N. Sakai, Y. Iwata, K. Kitagawa, Y. Ishida, T. Kondo, H. Hashimoto, Y. Ishiwata, N. Mukaida, et al. Gene Therapy via Blockade of Monocyte Chemoattractant Protein-1 for Renal Fibrosis J. Am. Soc. Nephrol., April 1, 2004; 15(4): 940 - 948. [Abstract] [Full Text] [PDF]

				Y. Liu Epithelial to Mesenchymal Transition in Renal Fibrogenesis: Pathologic Significance, Molecular Mechanism, and Therapeutic Intervention J. Am. Soc. Nephrol., January 1, 2004; 15(1): 1 - 12. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673