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

Abstract

Interaction between epithelial cells and mesenchymal cells is essential in normal organ morphogenesis and in tissue repair after injury. Epimorphin, a mesenchymal protein that regulates epithelial morphogenesis through epithelialmesenchymal interactions, has recently attracted attention as an important modulator of tissue repair. In this study we analyzed the role of epimorphin in renal fibrosis. We first found a progressive increase in epimorphin expression corresponding to the progression of renal fibrosis in mice with unilateral ureteral obstruction (UUO). To determine whether this expression has a role in the repair or progression of renal fibrosis, we analyzed a model of renal fibrosis repair, the UUO-release (UUO-R) model. Epimorphin expression was increased at 3 and 7 days after the UUO-R rather than on the day of release, but was decreased at 21 days after the release. Inhibition of endogenous epimorphin with antiepimorphin antibody (MC-1) significantly delayed the repair of fibrosis. When compared with normal-IgG-injected mice, MC-1-injected mice showed significantly decreased renal matrix metalloproteinase (MMP)-2 and MMP-9 expressions by western blotting and increased expression of TGF-b and collagen-I mRNA by real-time RT-PCR. Recombinant epimorphin induced prominent increases in MMP-2 and MMP-9 activities in the culture media of renal interstitial fibroblasts in vitro. These findings indicate that epimorphin has a pivotal role in the repair of renal fibrosis by modulating both extracellular matrix (ECM) degradation and its production.

Epimorphin Alters the Inhibitory Effects of SOX9 on Mmp13 in Activated Hepatic Stellate Cells

“…It has been associated with resolution of fibrosis in both kidney and liver by inducing protease expression to cause ECM degradation [22], [24]. In line with this, we detected altered MMP/TIMP expression in activated rHSCs treated with rhEPIM (Fig.…”

“…However, in models of liver regeneration, Epim also appears to increase later in HSCs highlighting a potential role during the recovery phase of tissue repair [21]–[23]. In line with this, a feature of EPIM in both renal and liver fibrosis is its ability to induce protease expression favoring collagen degradation and resolution of fibrosis [22], [24], [25]. Although this provides clues of EPIM's role in modulating the ECM in fibrosis the mechanisms by which it acts and is regulated are less clear.…”

Epimorphin deletion inhibits polyposis in theApcmin/+mouse model of colon carcinogenesis via decreased myofibroblast HGF secretion

“…Epim interacts with ␣V-integrins on target epithelial cells (13), affecting downstream signaling pathways that induce branching morphogenesis and regulating transcription of multiple target genes, including MMPs (6). Relevant to the present observations are studies in kidney that showed that Epim is expressed in interstitial myofibroblasts and Epim protein abundance increases in response to urinary obstructive injury; blocking Epim signaling with an anti-Epim antibody increases TGF-␤ mRNA expression in kidney during the injury recovery phase (36). Herein, we have shown that lack of Epim signaling in the gut in Apc min/ϩ mice also results in increased mucosal TGF-␤ expression.…”

“…For example, exposure of mammary epithelial cells to Epim resulted in increased expression of genes associated with branching morphogenesis in the mammary gland, such as matrix metalloproteinase (MMP)-3, and downregulation of luminal epithelial markers, such as keratin-16 (6). Also, administration of an anti-Epim-blocking antibody to mice in a kidney injury model resulted in increased transforming growth factor-␤ (TGF-␤) and decreased MMP-2 and MMP-9 expression (36).…”

Epimorphin−/− mice are protected, in part, from acute colitis via decreased interleukin 6 signaling

“…More recent studies suggest that consistent detection of this protein may be best achieved by immunostaining on frozen versus paraffin embedded sections. 41 …”