Matrix Metalloproteinase-7 as a Surrogate Marker Predicts Renal Wnt/β-Catenin Activity in CKD
Matrix Metalloproteinase-7 as a Surrogate Marker Predicts Renal Wnt/β-Catenin Activity in CKD
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DOI：
10.1681/asn.2011050490
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发表时间：
2012-02-01
影响因子：
13.6
通讯作者：
Liu, Youhua
中科院分区：
文献类型：
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作者：
He, Weichun;Tan, Roderick J.;Liu, Youhua
多种慢性肾脏疾病表现出Wnt/ β -连环蛋白信号的再激活。在一些组织中，β -连环蛋白转录调节基质金属蛋白酶-7 (MMP-7)，但慢性肾脏疾病中MMP-7与Wnt/ β -连环蛋白信号传导之间的关系尚不清楚。在阻塞性肾病和局灶节段性肾小球硬化（阿霉素肾病）的小鼠模型中，我们观察到MMP-7 mRNA和蛋白以时间依赖性的方式上调。在这些模型中，MMP-7诱导的模式和程度与Wnt/ β -catenin信号传导呈正相关。通过异位表达Wnt1激活β -连环蛋白可以促进体内MMP-7的表达，而传递编码内源性Wnt拮抗剂Dickkopf-1的基因则可以消除其诱导作用。尿中检测的MMP-7蛋白水平与肾Wnt/ β -连环蛋白活性相关。paricalcitol对Wnt/ β -连环蛋白信号通路的药物阻断抑制病变肾脏中MMP-7的表达，并降低尿中检测到的MMP-7水平。在体外，β -连环蛋白激活诱导肾上皮细胞中MMP-7的表达和分泌，并促进T细胞因子与MMP-7启动子的结合。我们还观察到，在各种肾病患者的肾组织中，MMP-7的表达水平较高，与β -连环蛋白相关。总之，肾脏MMP-7水平与Wnt/ β -连环蛋白活性相关，尿液MMP-7可能是肾脏中这种纤维化信号的非侵入性生物标志物。
A variety of chronic kidney diseases exhibit reactivation of Wnt/beta-catenin signaling. In some tissues, beta-catenin transcriptionally regulates matrix metalloproteinase-7 (MMP-7), but the association between MMP-7 and Wnt/beta-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/beta-catenin signaling in these models. Activation of beta-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/beta-catenin activity. Pharmacologic blockade of Wnt/beta-catenin signaling by paricalcitol inhibited MMP-7 expression in diseased kidneys and reduced the levels detected in the urine. In vitro, beta-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 beta-catenin, in kidney tissue from patients with various nephropathies. In summary, levels of renal MMP-7 correlate with Wnt/beta-catenin activity, and urinary MMP-7 may be a noninvasive biomarker of this profibrotic signaling in the kidney.