MMP7 damages the integrity of the renal tubule epithelium by activating MMP2/9 during ischemia-reperfusion injury
MMP7 damages the integrity of the renal tubule epithelium by activating MMP2/9 during ischemia-reperfusion injury
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DOI：
10.1007/s10735-020-09914-4
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发表时间：
2020-10-17
影响因子：
3.2
通讯作者：
Ye, Qifa
中科院分区：
文献类型：
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作者：
Hu, Qianchao;Lan, Jianan;Ye, Qifa
肾缺血再灌注损伤是泌尿外科常见的问题，肾小管尤其是近端肾小管极易受到缺血再灌注损伤。本研究通过RNA测序技术检测正常兔肾和IR兔肾组织中差异表达基因（DEG），初步确定基质金属蛋白酶7（MMP 7）在IR损伤过程中起重要作用。事实上，在兔模型中检测到时间依赖性的肾损伤促进，如通过MMP 2/7/9水平的增加和紧密连接蛋白-1（TJP 1）的减少所证明的。在人肾近曲小管上皮细胞（HK-2）模型中也证实了类似的结果。值得注意的是，MMP 7的下调通过抑制切割的MMP 2/9而不是pro-MMP 2/9蛋白的表达来影响MMP 2/9的活性，这直接减轻了HK-2模型中TJP 1的降解。相反，抑制MMP 2/9对MMP 7没有影响。此外，免疫共沉淀实验表明，敲低MMP 7抑制MMP 2/9和TJP 1之间的相互作用。总的来说，这项研究表明MMP 7可以作为肾小管损伤的早期生物标志物，并揭示了MMP 7可以通过激活MMP 2/9降解TJP 1来破坏肾小管上皮的完整性。
Renal ischemia-reperfusion (IR) injury is a common issue in urological surgery, and the renal tubules, particularly the proximal tubules, are extremely vulnerable to IR injury. In this work, we detected the differently expressed genes (DEGs) between normal rabbit kidneys and IR kidneys by RNA-sequencing, then identified that matrix metalloproteinase-7 (MMP7) played an important role in the progress of IR injury. Indeed, A time-dependent promotion of renal injury was detected in rabbit model, as demonstrated by the increased levels of MMP2/7/9, and the decreased of tight junction protein-1 (TJP1). Furtherly, similar results were confirmed in human renal proximal tubule epithelial (HK-2) cells model. Notably, downregulation of MMP7 affected the activity of MMP2/9 by suppressing expression of cleaved-MMP2/9 not the pro-MMP2/9 protein, which directly alleviated the degradation of TJP1 in HK-2 model. On the contrary, MMP7 had not been affected by inhibiting MMP2/9. In addition, coimmunoprecipitation assay showed that knockdown MMP7 restrained the interaction between MMP2/9 and TJP1. Collectively, this study suggested that MMP7 could serve as early biomarkers for renal tubular injury, and revealed that MMP7 could destroy the integrity of tubular epithelium through degrading TJP1 by activating MMP2/9.