Tubular Atrophy and Interstitial Fibrosis After Renal Transplantation Is Dependent on Galectin-3
Tubular Atrophy and Interstitial Fibrosis After Renal Transplantation Is Dependent on Galectin-3
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DOI：
10.1097/tp.0b013e318242f40a
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发表时间：
2012-03-15
期刊：
影响因子：
6.2
通讯作者：
Sethi, Tariq
中科院分区：
文献类型：
--
作者：
Dang, Zexu;MacKinnon, Alison;Sethi, Tariq
背景。慢性同种异体移植物损伤（Chronic allograft injury， CAI）以间质纤维化和肾小管萎缩为特征，导致移植物功能进行性下降，导致每年肾移植损失5%，并且无法进行特异性治疗。半乳糖凝集素-3 （gal-3）是一种在多种纤维化组织中表达的β -半乳糖苷结合凝集素，在肾、肝和肺模型中，缺乏gal-3的小鼠纤维化减少。本研究探讨了gal-3在CAI中的作用。我们采用小鼠CAI模型，其特点是BM12供体与C57BL/6受体株之间存在单一II类错配。同基因移植物作为对照（C57BL/6）。然后在C57BL/6背景下，在BM12供体和gal-3无供体之间进行移植。与同基因对照组相比，BM12肾移植到C57BL6小鼠体内与间质纤维化（P < 0.0001）、肾小管萎缩（P < 0.0001）和gal-3表达上调（P = 0.002）相关。与野生型对照组相比，将BM12肾脏移植到gal-3缺失小鼠体内，可显著保存小管（P = 0.008），减少间质纤维化（P = 0.01），降低肌成纤维细胞活化（P = 0.01）和I型胶原表达（P = 0.04）。在gal-3缺失的小鼠中，浸润的白细胞数量没有改变，但巨噬细胞活化标志物YM1的表达减少（P = 0.0001），循环cd4阳性T细胞数量减少（P = 0.01），白细胞介素-4表达减少（P = 0.02），提示gal-3促进肾移植纤维化的可能机制。我们的研究结果表明，gal-3在CAI中具有潜在的作用，这代表了一个潜在的令人兴奋的治疗靶点。
Background. Chronic allograft injury (CAI), characterized by interstitial fibrosis and tubular atrophy, leads to a progressive decline in graft function, resulting in the loss of 5% of renal transplants per annum, and eludes specific therapies. Galectin-3 (gal-3) is a beta-galactoside-binding lectin expressed in diverse fibrotic tissue, and mice deficient in gal-3 have reduced fibrosis in kidney, liver, and lung models. The role of gal-3 in CAI is examined in this study.Methods. We adopted a murine model of CAI, characterized by a single class II mismatch between BM12 donor and C57BL/6 recipient strains. Syngeneic transplants served as controls (C57BL/6). Transplants were then performed between BM12 donors and gal-3 null recipients on a C57BL/6 background.Results. Transplantation of BM12 kidneys into C57BL6 mice was associated with interstitial fibrosis (P < 0.0001), tubular atrophy (P < 0.0001), and upregulation in gal-3 expression (P = 0.002), compared with syngeneic controls. Transplanting BM12 kidneys into gal-3 null mice resulted in significant preservation of tubules (P = 0.008) and reduced interstitial fibrosis (P = 0.01), with decreased myofibroblast activation (P = 0.01) and collagen I expression (P = 0.04), compared with wild type controls. The number of infiltrating leukocytes was unaltered by abrogation of gal-3, but reduced expression of YM1 (P = 0.0001), a marker of alternative macrophage activation, along with a reduction in the number of circulating CD4-positive T cells (P = 0.01), and reduced expression of interleukin-4 (P = 0.02) in gal-3 null mice suggest possible mechanisms by which gal-3 may promote renal transplant fibrosis.Conclusion. Our results suggest a potential role for gal-3 in CAI, and this represents a potentially exciting therapeutic target.