Matrix Metalloproteinase-7 Is a Urinary Biomarker and Pathogenic Mediator of Kidney Fibrosis

• Published in: Journal of the American Society of Nephrology Vol. 28; no. 2; pp. 598 - 611
• Main Authors: Zhou, Dong, Tian, Yuan, Sun, Ling, Zhou, Lili, Xiao, Liangxiang, Tan, Roderick J., Tian, Jianwei, Fu, Haiyan, Hou, Fan Fan, Liu, Youhua
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 01.02.2017
• Subjects: Animals; Basic Research; beta Catenin - physiology; Biomarkers - urine; Fibrosis - urine; Humans; Kidney - pathology; Kidney Diseases - urine; Matrix Metalloproteinase 7 - urine; Mice; Renal Insufficiency, Chronic - urine; nephropathy; chronic kidney disease; MMP-7; Pathophysiology of Renal Disease and Progression; Wnt; renal fibrosis
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2016030354

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.