Two Distinct Isoforms of Matrix Metalloproteinase-2 Are Associated with Human Delayed Kidney Graft Function.
Two Distinct Isoforms of Matrix Metalloproteinase-2 Are Associated with Human Delayed Kidney Graft Function.
复制标题
基质金属蛋白酶-2的两个不同的同工型与人类延迟的肾移植功能有关。
DOI：
10.1371/journal.pone.0136276
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Lovett DH
中科院分区：
文献类型：
--
作者：
Wanga S;Ceron CS;Delgado C;Joshi SK;Spaulding K;Walker JP;Song S;Olson JL;Lovett DH
移植肾功能延迟恢复（DGF）是肾移植的常见并发症，特别是在移植来自死亡供体和扩展标准供体的肾时。DGF由肾小管上皮细胞损伤引起，并具有直接和长期后果。这些包括需要移植后透析，急性排斥反应的发生率增加，以及长期结局较差。DGF代表了肾急性缺血/再灌注损伤的最明显的临床实例之一。实验研究已经证明，缺血/再灌注损伤诱导基质金属蛋白酶-2（FL-MMP-2）的全长分泌型同种型以及启动先天免疫应答的细胞内N-末端截短的MMP-2同种型（NTT-MMP-2）的合成。我们假设两种MMP-2亚型介导DGF中的肾小管上皮细胞损伤。通过免疫组织化学（IHC）、原位杂交和qPCR分析10例活检对照和41例临床诊断为DGF的病例的存档肾活检切片的肾小管损伤程度、FL-MMP-2和NTT-MMP-2亚型的表达，以确定亚型丰度。转录丰度的差异与肾小管损伤评分相关。MMP-2介导的损伤的标志物包括TUNEL染色和评估管周毛细血管密度。肾小管上皮细胞FL-MMP-2和NTT-MMP-2的表达与肾小管损伤程度之间存在明显的相关性。MMP-2亚型在相同的肾小管段中检测到，并存在于肾小管损伤的部位。qPCR显示FL-MMP-2和NTT-MMP-2转录物均高度显著增加。统计学分析显示FL-MMP-2和NTT-MMP-2转录丰度与肾小管损伤程度之间存在高度显著的相关性，其中NTT-MMP-2具有最强的相关性。我们得出结论，两种不同的MMP-2亚型与DGF中的肾小管损伤相关，并为预防这种疾病提供了新的治疗靶点。
Delayed graft function (DGF) is a frequent complication of renal transplantation, particularly in the setting of transplantation of kidneys derived from deceased donors and expanded-criteria donors. DGF results from tubular epithelial cell injury and has immediate and long term consequences. These include requirement for post-transplantation dialysis, increased incidence of acute rejection, and poorer long-term outcomes. DGF represents one of the clearest clinical examples of renal acute ischemia/reperfusion injury. Experimental studies have demonstrated that ischemia/reperfusion injury induces the synthesis of the full length secreted isoform of matrix metalloproteinase-2 (FL-MMP-2), as well as an intracellular N-terminal truncated MMP-2 isoform (NTT-MMP-2) that initiates an innate immune response. We hypothesized that the two MMP-2 isoforms mediate tubular epithelial cell injury in DGF. Archival renal biopsy sections from 10 protocol biopsy controls and 41 cases with a clinical diagnosis of DGF were analyzed for the extent of tubular injury, expression of the FL-MMP-2 and NTT-MMP-2 isoforms by immunohistochemistry (IHC), in situ hybridization, and qPCR to determine isoform abundance. Differences in transcript abundance were related to tubular injury score. Markers of MMP-2-mediated injury included TUNEL staining and assessment of peritubular capillary density. There was a clear relationship between tubular epithelial cell expression of both FL-MMP-2 and NTT-MMP-2 IHC with the extent of tubular injury. The MMP-2 isoforms were detected in the same tubular segments and were present at sites of tubular injury. qPCR demonstrated highly significant increases in both the FL-MMP-2 and NTT-MMP-2 transcripts. Statistical analysis revealed highly significant associations between FL-MMP-2 and NTT-MMP-2 transcript abundance and the extent of tubular injury, with NTT-MMP-2 having the strongest association. We conclude that two distinct MMP-2 isoforms are associated with tubular injury in DGF and offer novel therapeutic targets for the prevention of this disorder.