Abstract—Matrix metalloproteinase-7 (MMP-7), a secreted zinc- and calcium-dependent endopeptidase, is a transcriptional target of canonical Wnt/β-catenin signaling. Because Wnt/β-catenin is activated in diseased kidney, we hypothesized that urinary MMP-7 level may be used as a noninvasive surrogate biomarker for fibrotic lesions. To test this hypothesis, we conducted a cross-sectional study, measuring urinary MMP-7 levels in a cohort of 102 patients with CKD. Compared with normal subjects, patients with various kidney disorders had markedly elevated urinary levels of MMP-7. Furthermore, urinary MMP-7 levels closely correlated with renal fibrosis scores in patients. In mice, knockout of MMP-7 ameliorated the fibrotic lesions and expression of matrix genes induced by obstructive injury. Genetic ablation of MMP-7 also preserved E-cadherin protein expression and substantially reduced the expression of total and dephosphorylated β-catenin and the de novo expression of vimentin and fibroblast-specific protein 1 in renal tubules of obstructed kidneys. In vitro, MMP-7 proteolytically degraded E-cadherin in proximal tubular cells, leading to β-catenin liberation and nuclear translocation and induction of β-catenin target genes by a mechanism independent of Wnt ligands. Finally, pharmacologic inhibition of MMP-7 immediately after obstructive injury reduced renal fibrosis in vivo These results suggest that MMP-7 not only can serve as a noninvasive biomarker but also is an important pathogenic mediator of kidney fibrosis.

Detail Information
Zhou D, Tian Y, Sun L, Zhou L, Xiao L, Tan RJ, Tian J, Fu H, Hou FF, and Liu Y. Matrix metalloproteinase-7 is a urinary biomarker and pathogenic mediator of kidney fibrosis. J Am Soc Nephrol. 2017. 28(2):598-611.