Centre for Inflammation Research, Queen's Medical Research Institute, Little France Crescent, Edinburgh, United Kingdom.
Transplantation. 2012 Mar 15;93(5):477-84. doi: 10.1097/TP.0b013e318242f40a.
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 β-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.
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.
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.
Our results suggest a potential role for gal-3 in CAI, and this represents a potentially exciting therapeutic target.
慢性同种异体移植物损伤（CAI）的特征是间质纤维化和肾小管萎缩，导致移植物功能逐渐下降，每年导致 5%的肾移植丢失，并且逃避特定的治疗方法。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，gal-3 缺乏的小鼠在肾脏、肝脏和肺模型中纤维化减少。本研究检查了 gal-3 在 CAI 中的作用。
我们采用了一种 CAI 小鼠模型，其特征是 BM12 供体和 C57BL/6 受体品系之间存在单一的 II 类错配。同基因移植作为对照（C57BL/6）。然后，在 C57BL/6 背景下，将 BM12 供体与 gal-3 缺失受体进行同种异体移植。
与同基因对照相比，将 BM12 肾脏移植到 C57BL6 小鼠中会导致间质纤维化（P<0.0001）、肾小管萎缩（P<0.0001）和 gal-3 表达上调（P=0.002）。将 BM12 肾脏移植到 gal-3 缺失小鼠中会导致肾小管明显保存（P=0.008）和间质纤维化减少（P=0.01），肌成纤维细胞激活减少（P=0.01）和胶原 I 表达减少（P=0.04）与野生型对照相比。通过消除 gal-3，浸润白细胞的数量没有改变，但替代型巨噬细胞激活的标志物 YM1 的表达减少（P=0.0001），以及循环 CD4 阳性 T 细胞的数量减少（P=0.01），以及白细胞介素-4（P=0.02）的表达减少在 gal-3 缺失小鼠中表明 gal-3 可能促进肾移植纤维化的可能机制。
我们的结果表明 gal-3 在 CAI 中可能发挥作用，这代表了一个潜在令人兴奋的治疗靶点。
