Abstract
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.
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Funding
This work was supported by the Medical Science Advancement Program (Clinical Medicine) of Wuhan University [Grant Numbers: TFLC2018003], National Science Foundation for Young Scientists of China [Grant Numbers: 81700657], and National Postdoctoral Program for Innovative Talents [Grant Numbers: BX201700177].
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HQC designed and carried out the research, analyzed the data, and wrote the manuscript. LJN, LWJ, CYW and CB helped to carry out the experiments and contributed ideas. LZZ, XY and WYF provided guidance and revised the manuscript. YQF and ZZB designed the experiments, provided overall guidance, and helped to write the manuscript.
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This study was approved by the Institutional Review Board/Ethics Committee of Zhongnan Hospital of Wuhan University. All animal experiments were carried out in accordance with Experimental Animal Management Ordinance (National Science and Technology Committee of China) and the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, Bethesda, MD, USA).
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Hu, Q., Lan, J., Liang, W. et al. MMP7 damages the integrity of the renal tubule epithelium by activating MMP2/9 during ischemia–reperfusion injury. J Mol Hist 51, 685–700 (2020). https://doi.org/10.1007/s10735-020-09914-4
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DOI: https://doi.org/10.1007/s10735-020-09914-4