title: Matrix metalloproteinase-7 as a surrogate marker predicts renal Wnt/β-catenin activity in CKD.
abstract: A variety of chronic kidney diseases exhibit reactivation of Wnt/β-catenin signaling. In some tissues, β-catenin transcriptionally regulates matrix metalloproteinase-7 (MMP-7), but the association between MMP-7 and Wnt/β-catenin signaling in chronic kidney disease is unknown. Here, in mouse models of both obstructive nephropathy and focal segmental glomerulosclerosis (adriamycin nephropathy), we observed upregulation of MMP-7 mRNA and protein in a time-dependent manner. The pattern and extent of MMP-7 induction were positively associated with Wnt/β-catenin signaling in these models. Activation of β-catenin through ectopic expression of Wnt1 promoted MMP-7 expression in vivo, whereas delivery of the gene encoding the endogenous Wnt antagonist Dickkopf-1 abolished its induction. Levels of MMP-7 protein detected in the urine correlated with renal Wnt/β-catenin activity. Pharmacologic blockade of Wnt/β-catenin signaling by paricalcitol inhibited MMP-7 expression in diseased kidneys and reduced the levels detected in the urine. In vitro, β-catenin activation induced the expression and secretion of MMP-7 and promoted the binding of T cell factor to the MMP-7 promoter in kidney epithelial cells. We also observed higher levels of MMP-7 expression, which correlated with β-catenin, in kidney tissue from patients with various nephropathies. In summary, levels of renal MMP-7 correlate with Wnt/β-catenin activity, and urinary MMP-7 may be a noninvasive biomarker of this profibrotic signaling in the kidney.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Weichun
authors.initials: W
authors.lastname: He
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Tan
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Li
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Nie
authors.forename: Fan Fan
authors.initials: FF
authors.lastname: Hou
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D015415:Biomarkers; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D002908:Chronic Disease; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism*; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000502:physiology* / Q000652:urine; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
chemical_list: D015415:Biomarkers; D015820:Cadherins; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D020783:Matrix Metalloproteinase 7
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