17267741

pubmed:Citation

3

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 alpha-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-beta. In vitro, addition of plasmin (20 microg/ml) to cultures of murine tubular epithelial cells initiated ERK phosphorylation within minutes, followed by phenotypic transition to fibroblast-specific protein-1+, alpha-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.

eng

IM

MEDLINE

1046-6673

Print

NLM

846-59

pubmed-meshheading:17267741-Actins, pubmed-meshheading:17267741-Animals, pubmed-meshheading:17267741-Butadienes, pubmed-meshheading:17267741-Cadherins, pubmed-meshheading:17267741-Cell Movement, pubmed-meshheading:17267741-Collagen, pubmed-meshheading:17267741-Disease Models, Animal, pubmed-meshheading:17267741-Enzyme Inhibitors, pubmed-meshheading:17267741-Extracellular Signal-Regulated MAP Kinases, pubmed-meshheading:17267741-Female, pubmed-meshheading:17267741-Fibrinolysin, pubmed-meshheading:17267741-Fibrosis, pubmed-meshheading:17267741-Kidney, pubmed-meshheading:17267741-Kidney Diseases, pubmed-meshheading:17267741-Male, pubmed-meshheading:17267741-Mice, pubmed-meshheading:17267741-Mice, Inbred C57BL, pubmed-meshheading:17267741-Mice, Knockout, pubmed-meshheading:17267741-Nitriles, pubmed-meshheading:17267741-Phosphorylation, pubmed-meshheading:17267741-Plasminogen Activator Inhibitor 1, pubmed-meshheading:17267741-Receptor, PAR-1, pubmed-meshheading:17267741-Signal Transduction, pubmed-meshheading:17267741-Transforming Growth Factor beta, pubmed-meshheading:17267741-Ureteral Obstruction

Plasmin(ogen) promotes renal interstitial fibrosis by promoting epithelial-to-mesenchymal transition: role of plasmin-activated signals.

Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural