Cardiology, Department of Medicine.
Surgery.
Cardiovasc Res. 2017 Nov 1;113(13):1551-1559. doi: 10.1093/cvr/cvx177.
Chronic kidney disease (CKD) is a powerful independent risk factor for cardiovascular events, including vein graft failure. Because CKD impairs the clearance of small proteins, we tested the hypothesis that CKD exacerbates vein graft disease by elevating serum levels of critical cytokines that promote vein graft neointimal hyperplasia.
We modelled CKD in C57BL/6 mice with 5/6ths nephrectomy, which reduced glomerular filtration rate by 60%, and we modelled vein grafting with inferior-vena-cava-to-carotid interposition grafting. CKD increased vein graft neointimal hyperplasia four-fold, decreased vein graft re-endothelialization two-fold, and increased serum levels of interleukin-9 (IL-9) five-fold. By quantitative immunofluorescence and histochemical staining, vein grafts from CKD mice demonstrated a ∼two-fold higher prevalence of mast cells, and a six-fold higher prevalence of activated mast cells. Concordantly, vein grafts from CKD mice showed higher levels of TNF and NFκB activation, as judged by phosphorylation of NFκB p65 on Ser536 and by expression of VCAM-1. Arteriovenous fistula veins from humans with CKD also showed up-regulation of mast cells and IL-9. Treating CKD mice with IL-9-neutralizing IgG reduced vein graft neointimal area four-fold, increased vein graft re-endothelialization ∼two-fold, and reduced vein graft total and activated mast cell levels two- and four-fold, respectively. Treating CKD mice with the mast cell stabilizer cromolyn reduced neointimal hyperplasia and increased re-endothelialization in vein grafts. In vitro, IL-9 promoted endothelial cell apoptosis but had no effect on smooth muscle cell proliferation.
CKD aggravates vein graft disease through mechanisms involving IL-9 and mast cell activation.
慢性肾脏病（CKD）是心血管事件的一个强有力的独立危险因素，包括静脉移植物失败。由于 CKD 会损害小蛋白的清除，因此我们通过测试假设来检验 CKD 是否通过提高促进静脉移植物内膜增生的关键细胞因子的血清水平来加重静脉移植物疾病。
我们通过 5/6 肾切除术在 C57BL/6 小鼠中构建 CKD 模型，该模型使肾小球滤过率降低 60%，并通过下腔静脉-颈动脉间置移植术构建静脉移植物模型。CKD 使静脉移植物内膜增生增加了四倍，使静脉移植物再内皮化减少了两倍，并使血清中白细胞介素 9（IL-9）的水平增加了五倍。通过定量免疫荧光和组织化学染色，CKD 小鼠的静脉移植物中，肥大细胞的患病率增加了约两倍，活化的肥大细胞的患病率增加了六倍。相应地，通过 NFκB p65 的丝氨酸 536 磷酸化和 VCAM-1 的表达来判断，CKD 小鼠的静脉移植物显示出更高水平的 TNF 和 NFκB 激活。来自 CKD 患者的动静脉瘘静脉也显示出肥大细胞和 IL-9 的上调。用 IL-9 中和 IgG 治疗 CKD 小鼠可使静脉移植物内膜面积减少四倍，使静脉移植物再内皮化增加约两倍，并分别使静脉移植物总肥大细胞和活化肥大细胞水平减少两倍和四倍。用肥大细胞稳定剂色甘酸钠治疗 CKD 小鼠可减少静脉移植物的内膜增生并增加其再内皮化。在体外，IL-9 促进内皮细胞凋亡，但对平滑肌细胞增殖没有影响。
CKD 通过涉及 IL-9 和肥大细胞激活的机制加重静脉移植物疾病。
