During EMT, renal epithelial cells are transformed into mesenchymal cells. These mesenchymal cells ameliorate tissue damage, causing the accumulation of ECM and the production of myofibroblasts, which are key effectors in ECM synthesis and deposition. EMT is characterized by reduced cell-cell contact, reduced expression of epithelial markers such as E-cadherin, and increased expression of mesenchymal markers such as α-SMA, type I collagen, and fibronectin (Son and Moon, 2010). Although many studies have shown that EMT in the kidney may lead to renal fibrosis, the relationship between EMT and renal fibrosis remains controversial (Menon and Ross, 2016).

MMP-7 mediates tubular epithelial-interstitial fibroblast communication through Wnt/β-catenin signaling (Zhou et al., 2013, Figure 1), an evolutionarily conserved pathway that regulates cell fate, organ development, and tissue homeostasis, as well as injury and repair. Wnt/β-catenin signaling is relatively silent in the normal adult kidney but is activated after renal injury in a wide variety of animal models and human kidney disorders (Clevers and Nusse, 2012). Canonical Wnt signaling activation leads to β-catenin stabilization and nuclear translocation, followed by binding of β-cateninto T cell factor (TCF)/lymphoidenhancer–binding factor to stimulate the transcription of Wnt target genes, a common pathological occurrence in a wide variety of CKDs (Nelson et al., 2011). Tubular activation of β-catenin after injury leads to EMT and upregulates tubular expression and secretion of MMP-7 (Liu, 2010; He et al., 2012). As a result, secreted MMP-7 induces the expression of FasL, a key player in the extrinsic, receptor-mediated apoptosis pathway (Villa-Morales and Fernandez-Piqueras, 2012), in interstitial fibroblasts and potentiates apoptosis of these cells (Zhou et al., 2013). Loss of tubular β-catenin results in enhanced interstitial fibroblast survival due to decreased MMP-7 expression (Zhou et al., 2013).

MMP-7 induces E-cadherin proteolytic degradation and β-catenin signaling activation independent of Wnt to promote EMT (McGuire et al., 2003; Zhou et al., 2016). E-cadherin is an epithelial cell adhesion receptor essential for the maintenance of tubular epithelial integrity. E-cadherin destruction is the initial step during EMT and disrupts tubular epithelial cell integrity (Liu, 2004). Shibata et al. (2009) found that MMP-7 reduces E-cadherin levels and promotes EMT in diseased kidneys, contributing to tubular epithelial injury (Zhou et al., 2013). One consequence of MMP-7-mediated E-cadherin degradation is β-catenin liberation independent of Wnt (Zhou et al., 2016). The liberated β-catenin then translocates into the nucleus as a transcription regulator and drives the expression of target genes, including MMP-7(He et al., 2010; Tan and Liu, 2012). An MMP-7-knockout mouse model showed that MMP-7 is an important pathogenic mediator that triggers the activation of β-catenin signaling and promotes renal fibrosis (Zhou et al., 2016).

MMP-7 also degrades collagen type IV and laminin to induce EMT (Tan and Liu, 2012, Figure 1). MMP-7 cleaves not only elastin but also many other ECM substrates, such as collagen type IV and laminin (Sbardella et al., 2012), which are the major components of the tubular basement membrane (TBM). Increased MMP-7 aggravates TBM damage, which facilitates tubular EMT in fibrotic kidneys (Tan and Liu, 2012).

Advanced CKD is characterized by chronic hypoxia in the renal interstitium (Mimura and Nangaku, 2010). Hypoxia can lead to tubular EMT or apoptosis, activate resident fibroblasts and impair peritubular capillaries, creating a cycle of chronic hypoxia and resulting in renal fibrosis (Liu, 2011). MMP-7 is a major MMP activator in conditioned medium of hypoxic bladder smooth muscle cells (BSMCs) and is also transcriptionally induced at 6 h of hypoxia in an Erkl/2-dependent manner (Sabha et al., 2006). In addition, MMP-7 is upregulated in macrophages at sites of inflammation, such as wounds and tumors, in response to hypoxia (Crowther et al., 2001). The increase in the ratio of active (18 kDa) to inactive (28 kDa) MMP-7 coincides with the peak period of hypoxia-induced Erkl/2 activation. Moreover, hypoxia activates β-catenin in human macrophages by inducing MMP-7mRNA expression (Deguchi et al., 2009).

TGF-β is a pleiotropic cytokine that plays an important role in cell proliferation and differentiation and induces the synthesis of ECM components. TGF-β is also a major cytokine/growth factor involved in renal fibrosis (Meng et al., 2012). Smad proteins are highly conserved transcription factors that mediate numerous effects of the TGF-β superfamily (Massague, 2012). TGF-β1 stimulates renal tubular EMT, which is a crucial process in tubulointerstitial fibrosis development (Carew et al., 2012).

Recent studies have revealed the existence of a close relationship between MMP-7 and TGF-β signaling (Figure 2). Li et al. (2017) observed that the expression of TGF-β1 and MMP-7 are upregulated in STZ-induced diabetic nephropathy rats but markedly decreased in diabetic nephropathy rats treated with sodium hydrosulfide (Li et al., 2017), which suggests regulation between TGF-β and MMP-7. MMP-7 is also closely related to TGF-β/Smad4 signaling (Xiao et al., 2016). Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent class III deacetylase that can deacetylate both histone and non-histone proteins, has been shown to participate in numerous cellular processes by deacetylating specific substrates. In particular, SIRT1 has shown reno protective effects in several models of acute kidney injury (Fan et al., 2013) and chronic kidney diseases (Hasegawa et al., 2013). SIRT1 inhibits MMP-7 protein expression by deacetylating Smad4, a transcription factor for MMP-7 expression, whereas SIRT1 inhibition induces MMP-7 upregulation (Xiao et al., 2016). Simic et al. (2013) found that TGF-β regulates MMP-7 expression, whereas SIRT1 deacetylates Smad4 and represses MMP-7 activity. SIRT1 regulates MMP-7 expression and enzyme activity via Smad4 deacetylation. Moreover, Thiery et al. (2009) found that TGF-β-induced β-catenin is required for the synthesis of a-SMA, a marker of EMT, in renal proximal tubular cells. Moreover, β-catenin promotes EMT further by upregulating MMP-7(Zhou et al., 2013). However, TGF-β suppresses the expression of several MMPs by binding of the c-fos proto-oncogene product Fos protein to TGF-β inhibitory elements in the promoter regions of MMP genes (Kerr et al., 1990). McLennan et al. (2007) found that MMP-7 levels are reduced in streptozotocin-induced diabetic nephropathy rats via TGF-β-dependent mechanisms; thus, TGF-β induction may contribute to reductions in MMP-7 expression and ECM accumulation in diabetic nephropathy.

Interestingly, an MMP-7/syndecan-1/TGF-β1 autocrine loop leading to TGF-β1 production has been identified in hepatocellular carcinoma (Zeng et al., 2016). Further studies are needed to investigate whether a similar loop exists in renal fibrosis.

Aberrant thickening of the glomerular basement membrane (GBM) and TBM, as well as excessive accumulation of mesangial matrices in renal fibrosis, is the result of an imbalance between the synthesis and degradation of ECM components. ECM deposition in renal structures, such as the glomerular capillary wall, arterioles, mesangium, and tubule-interstitial space, will ultimatelycause renal fibrosis (Duffield, 2014). The major ECM component perturbations that occur in the GBM include increases in collagen type IV (α 3 and α 4 chains), laminin and fibronectin expression (Hu et al., 2015). The molecules involved in increased ECM deposition in kidney fibrosis have been investigated extensively, especially MMP-7 (Xu et al., 2014).

MMP-7 can alter the micro-architecture of the glomerular apparatus and degrades collagen type IV, small proteoglycans, fibronectin, laminin, and entactin, all of which are components of the glomerular ECM (Tan and Liu, 2012). In addition, MMP-7 enhances the actions of growth factors. For instance, aberrant renal growth is preceded by a marked increase in the expression of intra-renal insulin-like growth factor (IGF)-I protein, which is trafficked into the kidney as a result of changes in IGF-binding protein (IGFBP) expression within renal tissues rather than enhancements in local IGF-I production (Flyvbjerg, 2000). Specifically, induction of IGFBP-1, 3, and 5 expression has been demonstrated in early renal hypertrophy in streptozotocin-treated diabetic rats (Park et al., 1998). Consequently, MMP-7 overproduction in kidney parenchyma may result in enhanced degradation of IGFBPs and the release of free bioactive IGFs, leading to expansion of the mesangium. MMP-7 has been shown to proteolytically degrade IGFBP-3 and IGFBP-5, and IGFBP cleavage by MMP-7 can liberate IGF-II (Miyamoto et al., 2004; Hemers et al., 2005; McCaig et al., 2006). Moreover, increased Col1a2 and Col3a1 expression are correlated with fibrotic changes in the kidney (Fragiadaki et al., 2011). A recent study reported that early MMP-7 upregulation increases Col1a2 and Col3a1 transcription primarily via PIK3, p38, ERK, Src, and PKA signaling, leading to subsequent collagen deposition in the kidney (Oelusarz et al., 2013). Taken together, these data suggest thatMMP-7 activity may contribute, either directly or indirectly, to GBM thickening and mesangial expansion, which precede the onset of kidney fibrotic lesions.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.