ABSTRACT
A variety of chronic kidney diseases exhibit reactivation of Wnt/b-catenin signaling. In some tissues,
b-catenin transcriptionally regulates matrix metalloproteinase-7 (MMP-7), but the association between
MMP-7 and Wnt/b-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 ofMMP-7mRNA and protein in a time-dependent manner. The pattern and extent ofMMP-7
induction were positively associated withWnt/b-catenin signaling in these models. Activation of b-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/b-catenin activity. Pharmacologic blockade of Wnt/
b-catenin signaling by paricalcitol inhibitedMMP-7 expression in diseased kidneys and reduced the levels
detected in the urine. In vitro, b-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 b-catenin, in kidney tissue from patients with
various nephropathies. In summary, levels of renal MMP-7 correlate with Wnt/b-catenin activity, and
urinary MMP-7 may be a noninvasive biomarker of this profibrotic signaling in the kidney.