Zhou Dong, Tian Yuan, Sun Ling, Zhou Lili, Xiao Liangxiang, Tan Roderick J, Tian Jianwei, Fu Haiyan, Hou Fan Fan, Liu Youhua
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.
J Am Soc Nephrol. 2017 Feb;28(2):598-611. doi: 10.1681/ASN.2016030354. Epub 2016 Sep 13.
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.
基质金属蛋白酶-7（MMP-7）是一种分泌型的锌和钙依赖性内肽酶，是经典Wnt/β-连环蛋白信号通路的转录靶点。由于Wnt/β-连环蛋白在患病肾脏中被激活，我们推测尿MMP-7水平可作为纤维化病变的非侵入性替代生物标志物。为了验证这一假设，我们进行了一项横断面研究，测量了102例慢性肾脏病患者队列中的尿MMP-7水平。与正常受试者相比，患有各种肾脏疾病的患者尿MMP-7水平显著升高。此外，患者的尿MMP-7水平与肾纤维化评分密切相关。在小鼠中，敲除MMP-7可改善梗阻性损伤诱导的纤维化病变和基质基因表达。MMP-7的基因敲除还可保留E-钙黏蛋白的蛋白表达，并显著降低梗阻性肾脏肾小管中总β-连环蛋白和去磷酸化β-连环蛋白的表达以及波形蛋白和成纤维细胞特异性蛋白1的新生表达。在体外，MMP-7可蛋白水解降解近端肾小管细胞中的E-钙黏蛋白，导致β-连环蛋白释放和核转位，并通过一种独立于Wnt配体的机制诱导β-连环蛋白靶基因表达。最后，在梗阻性损伤后立即对MMP-7进行药物抑制可减轻体内肾纤维化。这些结果表明，MMP-7不仅可作为非侵入性生物标志物，而且是肾纤维化的重要致病介质。
