Matrix Metalloproteinase-7 Is a Urinary Biomarker and Pathogenic Mediator of Kidney Fibrosis
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 bioma...
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| Published in | Journal of the American Society of Nephrology Vol. 28; no. 2; pp. 598 - 611 |
|---|---|
| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Society of Nephrology
01.02.2017
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| Subjects | |
| Online Access | Get full text |
| ISSN | 1046-6673 1533-3450 |
| DOI | 10.1681/ASN.2016030354 |
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| 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. |
|---|---|
| AbstractList | 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. 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. |
| Author | Tian, Yuan Zhou, Lili Sun, Ling Fu, Haiyan Hou, Fan Fan Xiao, Liangxiang Tian, Jianwei Liu, Youhua Tan, Roderick J. Zhou, Dong |
| Author_xml | – sequence: 1 givenname: Dong surname: Zhou fullname: Zhou, Dong organization: Department of Pathology and – sequence: 2 givenname: Yuan surname: Tian fullname: Tian, Yuan organization: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China – sequence: 3 givenname: Ling surname: Sun fullname: Sun, Ling organization: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China – sequence: 4 givenname: Lili surname: Zhou fullname: Zhou, Lili organization: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China – sequence: 5 givenname: Liangxiang surname: Xiao fullname: Xiao, Liangxiang organization: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China – sequence: 6 givenname: Roderick J. surname: Tan fullname: Tan, Roderick J. organization: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and – sequence: 7 givenname: Jianwei surname: Tian fullname: Tian, Jianwei organization: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China – sequence: 8 givenname: Haiyan surname: Fu fullname: Fu, Haiyan organization: Department of Pathology and – sequence: 9 givenname: Fan Fan surname: Hou fullname: Hou, Fan Fan organization: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China – sequence: 10 givenname: Youhua surname: Liu fullname: Liu, Youhua organization: Department of Pathology and, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27624489$$D View this record in MEDLINE/PubMed |
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| Keywords | nephropathy chronic kidney disease MMP-7 Pathophysiology of Renal Disease and Progression Wnt renal fibrosis |
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-catenin signaling.... Matrix metalloproteinase-7 (MMP-7), a secreted zinc- and calcium-dependent endopeptidase, is a transcriptional target of canonical Wnt/β-catenin signaling.... |
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| SubjectTerms | 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 |
| Title | Matrix Metalloproteinase-7 Is a Urinary Biomarker and Pathogenic Mediator of Kidney Fibrosis |
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