1] Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada [2] Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
Kidney Int. 2014 Jan;85(1):82-93. doi: 10.1038/ki.2013.225. Epub 2013 Jun 12.
Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of matrix metalloproteinases (MMPs). While TIMP2 and TIMP3 inhibit MMPs, TIMP3 also inhibits activation of pro-MMP2, whereas TIMP2 promotes it. Here we assessed the differential role of TIMP2 and TIMP3 in renal injury using the unilateral ureteral obstruction model. Gene microarray assay showed that post obstruction, the lack of TIMP3 had a greater impact on gene expression of intermediate, late injury- and repair-induced transcripts, kidney selective transcripts, and solute carriers. Renal injury in TIMP3(-/-), but not in TIMP2(-/-), mice increased the expression of collagen type I/III, connective tissue growth factor, transforming growth factor-β, and the downstream Smad2/3 pathway. Interestingly, ureteral obstruction markedly increased MMP2 activation in the kidneys of TIMP3(-/-) mice, which was completely blocked in the kidneys of TIMP2(-/-) mice. These changes are consistent with enhanced renal tubulointerstitial fibrosis in TIMP3(-/-) and its reduction in TIMP2(-/-) mice. The activities of tumor necrosis factor-α-converting enzyme, caspase-3, and mitogen-activated kinases were elevated in the kidneys of TIMP3(-/-) mice but not TIMP2(-/-) mice, suggesting enhanced activation of apoptotic and pathological signaling pathways only in the obstructed kidney of TIMP3(-/-) mice. Thus, TIMP2 and TIMP3 play differential and contrasting roles in renal injury: TIMP3 protects from damage, whereas TIMP2 promotes injury through MMP2 activation.
组织金属蛋白酶抑制剂（TIMPs）是基质金属蛋白酶（MMPs）的内源性抑制剂。TIMP2 和 TIMP3 抑制 MMPs，而 TIMP3 还抑制 pro-MMP2 的激活，而 TIMP2 促进其激活。在这里，我们使用单侧输尿管梗阻模型评估了 TIMP2 和 TIMP3 在肾损伤中的差异作用。基因微阵列分析表明，梗阻后，缺乏 TIMP3 对中间、晚期损伤和修复诱导转录物、肾脏选择性转录物和溶质载体的基因表达有更大的影响。TIMP3(-/-) 小鼠的肾损伤增加了胶原类型 I/III、结缔组织生长因子、转化生长因子-β 和下游 Smad2/3 途径的表达，但 TIMP2(-/-) 小鼠的肾损伤没有增加。有趣的是，输尿管梗阻显著增加了 TIMP3(-/-)小鼠肾脏中 MMP2 的激活，而 TIMP2(-/-)小鼠肾脏中的 MMP2 激活则完全被阻断。这些变化与 TIMP3(-/-)小鼠肾间质纤维化增强及其在 TIMP2(-/-)小鼠中的减少一致。TIMP3(-/-)小鼠肾脏中的肿瘤坏死因子-α转换酶、半胱天冬酶-3 和有丝分裂原激活蛋白激酶的活性升高，但 TIMP2(-/-)小鼠的活性没有升高，这表明只有 TIMP3(-/-)小鼠的梗阻肾脏中增强了凋亡和病理信号通路的激活。因此，TIMP2 和 TIMP3 在肾损伤中发挥不同的、相反的作用：TIMP3 保护免受损伤，而 TIMP2 通过 MMP2 激活促进损伤。
