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Plasmin(ogen) Promotes Renal Interstitial Fibrosis by Promoting Epithelial-to-Mesenchymal Transition: Role of Plasmin-Activated Signals

Guoqiang Zhang^*, Kelly A. Kernan^*, Sarah J. Collins^*, Xiaohe Cai^*, Jesús M. López-Guisa^*, Jay L. Degen, Yigal Shvil and Allison A. Eddy^*

^* Division of Nephrology, University of Washington and Children’s Hospital and Regional Medical Center, Seattle, Washington; Division of Basic Science Research, Children’s Hospital Research Foundation, Cincinnati, Ohio; and Hebrew University-Hadassah School of Medicine, Jerusalem, Israel

Address correspondence to: Dr. Allison A. Eddy, Children’s Hospital & Regional Medical Center, 4800 Sand Point Way NE, Division of Nephrology, Mail Stop M1-5, Seattle, WA 98105. Phone: 206-987-2524; Fax: 206-987-2636; E-mail: allison.eddy{at}seattlechildrens.org

Received for publication August 22, 2006. Accepted for publication December 29, 2006.

Plasminogen (Plg) activator inhibitor-1 (PAI-1) is an important fibrosis-promoting molecule. Whether this effect can be attributed to PAI-1’s activity as an inhibitor of plasmin generation is debated. This study was designed to investigate the role of Plg in renal fibrosis using in vivo and in vitro approaches. Plg-deficient (Plg–/–) and wild-type (Plg+/+) C57BL/6 mice were subjected to unilateral ureteral obstruction or sham surgery (n = 8/group; sham, days 3, 7, 14, and 21). Plg deficiency was confirmed by the absence of Plg mRNA, protein, and plasmin activity. After 21 d of unilateral ureteral obstruction, total kidney collagen was significantly reduced by 35% in the Plg–/– mice. Epithelial-to-mesenchymal transition (EMT), as typified by tubular loss of E-cadherin and acquisition of -smooth muscle actin, was also significantly reduced in Plg–/– mice, 76% and 50%, respectively. Attenuation of EMT and fibrosis severity in the Plg–/– mice was associated with significantly lower levels of phosphorylated extracellular signal–regulated kinase (ERK) and active TGF-. In vitro, addition of plasmin (20 µg/ml) to cultures of murine tubular epithelial cells initiated ERK phosphorylation within minutes, followed by phenotypic transition to fibroblast-specific protein-1+, -smooth muscle actin+, fibronectin-producing fibroblast-like cells. Both plasmin-induced ERK activation and EMT were significantly blocked in vitro by the protease-activated receptor-1 (PAR-1) silencing RNA; by pepducin, a specific anti–PAR-1 signaling peptide; and by the ERK kinase inhibitor UO126. Plasmin-induced ERK phosphorylation was enhanced in PAR-1–overexpressing tubular cells. These findings support important profibrotic roles for plasmin that include PAR-1–dependent ERK signaling and EMT induction.

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