Plasmin(ogen) Promotes Renal Interstitial Fibrosis by Promoting Epithelial-to-Mesenchymal Transition

Abstract

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 g/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.

Early Epithelial Phenotypic Changes Predict Graft Fibrosis

“…13,[33][34][35][36] Antagonizing EMT with bone morphogenic protein-7 or with hepatocyte growth factor has been shown to prevent the progression of renal fibrosis or even to induce its regression. 35,36 Before migrating into the interstitium, tubular epithelial cells are thought to switch from an epithelial to a mesenchymal phenotype.…”

Involvement of epimorphin in the repair of experimental renal fibrosis in mice

“…10,12,14,15 The importance of epithelial-mesenchymal transition in the development of renal fibrosis has been extensively analyzed and characterized. 2,[16][17][18][19][20][21][22] However, there have been no reports of studies analyzing the involvement of epimorphin, which is the key molecule for epithelial-mesenchymal interaction, in renal fibrosis. Moreover, we have not found reports of any studies examining epimorphin expression in diseased kidneys.…”

“…We used unilateral ureteral obstruction (UUO) in mice as a model of progressive renal fibrosis, [22][23][24] and used UUO-release (UUO-R) 25 as a model of fibrosis repair. We also evaluated the effect of anti-epimorphin antibody on the repair of renal fibrosis in UUO-R kidneys.…”

The Antifibrinolytic Drug Tranexamic Acid Reduces Liver Injury and Fibrosis in a Mouse Model of Chronic Bile Duct Injury

“…In contrast, TA treatment did not inhibit induction of ITGB6 mRNA, a component of the a V b 6 integrin that activates latent TGFb1. Although TA treatment did not affect expression of TGFb1 mRNA levels, plasmin has been shown to enzymatically activate latent TGFb1 (Lyons et al, 1990;Khalil et al, 1996), and plasmin-catalyzed TGFb1 activation has been implicated in other models of fibrosis (Lyons et al, 1990;Zhang et al, 2007). Collectively, additional studies investigating plasmin-driven profibrogenic protein expression and function are required, as these studies suggest multiple mechanisms whereby TA could inhibit liver fibrosis.…”