Matrix Metalloproteinases-7 and Kidney Fibrosis

Abstract

Matrix metalloproteinase-7 (MMP-7) is a secreted zinc- and calcium-dependent endopeptidase that degrades a broad range of extracellular matrix substrates and additional substrates. MMP-7 playsa crucial role in a diverse array of cellular processes and appears to be a key regulator of fibrosis in several diseases, including pulmonary fibrosis, liver fibrosis, and cystic fibrosis. In particular, the relationship between MMP-7 and kidney fibrosis has attracted significant attention in recent years. Growing evidence indicates that MMP-7 plays an important role in the pathogenesis of kidney fibrosis. Here, we summarize the recent progress in the understanding of the role of MMP-7 in kidney fibrosis. In particular, we discuss how MMP-7 contributes to kidney fibrotic lesions via the following three pathways: epithelial-mesenchymal transition (EMT), transforming growth factor-beta (TGF-β) signaling, and extracellular matrix (ECM) deposition. Further dissection of the crosstalk among and regulation of these pathways will help clinicians and researchers develop effective therapeutic approaches for treating chronic kidney disease.

Keywords: MMP-7; TGF-β; epithelial-mesenchymal transition; extracellular matrix.

Figure 1

MMP-7, which is expressed upon β-catenin activation, mediates EMT through the following 3 pathways. (A) Inducing FasL expression in interstitial fibroblasts and potentiating their apoptosis. (B) Inducing tubular epithelial integrity destruction by regulating E-cadherin degradation. (C) Inducing TBM destruction by degrading collagen type IV and laminin.

Figure 2

Two molecular pathways may be involved in the mechanisms by which TGF-β regulates MMP-7 expression. (A) TGF-β can induce β-catenin expression directly. (B) Smad4 deacetylation can suppress MMP-7 expression by promoting the binding of the Fos protein complex to the TGF-β inhibitory element, indicating that normal Smad4 can induce MMP-7 expression via TGF-β signaling.