Dissection of Key Events in Tubular Epithelial to Myofibroblast Transition and Its Implications in Renal Interstitial Fibrosis

Abstract

Myofibroblast activation is a key event playing a critical role in the progression of chronic renal disease. Emerging evidence suggests that myofibroblasts can derive from tubular epithelial cells by an epithelial to mesenchymal transition (EMT); however, the details regarding the conversion between these two cell types are poorly understood. Here we dissect the key events during the process of EMT induced by transforming growth factor-beta1. Incubation of human tubular epithelial cells with transforming growth factor-beta1 induced de novo expression of alpha-smooth muscle actin, loss of epithelial marker E-cadherin, transformation of myofibroblastic morphology, and production of interstitial matrix. Time-course studies revealed that loss of E-cadherin was an early event that preceded other alterations during EMT. The transformed cells secreted a large amount of matrix metalloproteinase-2 that specifically degraded tubular basement membrane. They also exhibited an enhanced motility and invasive capacity. These alterations in epithelial phenotypes in vitro were essentially recapitulated in a mouse model of renal fibrosis induced by unilateral ureteral obstruction. Hence, these results indicate that tubular epithelial to myofibroblast transition is an orchestrated, highly regulated process involving four key steps including: 1) loss of epithelial cell adhesion, 2) de novo alpha-smooth muscle actin expression and actin reorganization, 3) disruption of tubular basement membrane, and 4) enhanced cell migration and invasion.

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

“…TGF-b is a key mediator in kidney fibrosis and epithelialmesenchymal transition. 18,19,21 In this study TGF-b mRNA expression was significantly higher in MC-1-treated mice than in control mice. Collagen I and III mRNA expression levels were also higher in MC-1-treated mice than in control mice, but the difference in collagen III between groups did not reach statistical difference.…”

“…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.…”

Transforming Growth Factor-ॆ1 Potentiates Renal Tubular Epithelial Cell Death by a Mechanism Independent of Smad Signaling

“…However, sustained activation of TGF-␤1 signaling followed by secondary death challenges, a situation that presumably occurs under chronically injured conditions (32), could have lethal consequence to the tubular cells. Our two-hit working model is supported by the in vivo observation that the expression of both TGF-␤1 and its type I receptor is specifically up-regulated in renal tubules of the obstructed kidneys (12,32). Furthermore, this tubulespecific induction of TGF-␤1 axis is an early event that takes place at 1 day after ureteral obstruction (32), a timing that precedes significant cell apoptosis in the kidneys.…”

Basigin/CD147 Promotes Renal Fibrosis after Unilateral Ureteral Obstruction

“…54,55 As a result, TECs lose their polarity and acquire contractile motility. 55 Considering that TECs have a TGF-␤ receptor and produce MMP-2 and MMP-9 on TGF-␤ stimulation, 56 our data suggest that Bsg on TECs (an inducer of both MMP-2 and MMP-9) is at least partly responsible for disrupting tubular basement membrane and matrix remodeling by MMP induction.…”