Homocysteine Aggravates Intestinal Epithelial Barrier Dysfunction in Rats with Experimental Uremia
Homocysteine Aggravates Intestinal Epithelial Barrier Dysfunction in Rats with Experimental Uremia
复制标题
同型半胱氨酸加重实验性尿毒症大鼠的肠上皮屏障功能障碍
DOI：
10.1159/000494018
复制
发表时间：
2018-01-01
影响因子：
2.8
通讯作者：
Jiang, Hongli
中科院分区：
文献类型：
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作者：
Liang, Shanshan;Liu, Sixiu;Jiang, Hongli
背景/目的：先前的研究表明同型半胱氨酸（Hcy）是一种重要的肠源性尿毒症毒素。然而，Hcy 是否参与尿毒症中观察到的上皮屏障功能障碍仍不清楚。本研究旨在探讨Hcy对腺嘌呤诱导尿毒症大鼠肠道通透性及肠道屏障结构和功能的影响。方法：将Sprague-Dawley大鼠分为5组：正常对照组（NC组）、Hcy（H组）、尿毒症组（U组）、尿毒症+Hcy（UH组）、尿毒症+Hcy+VSL#3（UHV组）。腺嘌呤灌胃诱导实验性尿毒症，皮下注射Hcy。评估动物模型的肾功能和病理组织染色。苏木精伊红染色及电镜观察肠组织病理变化。评估血清和肠组织中同型半胱氨酸（Hcy）、白细胞介素（IL）-6、肿瘤坏死因子（TNF）-α、超氧化物歧化酶（SOD）和丙二醛（MDA）的水平以及血清内毒素和肠道通透性。通过蛋白质印迹法评估紧密连接蛋白claudin-1、occludin 和小带occlusionns-1 (ZO-1) 的水平。结果：血液分析和肾脏病理表明实验性尿毒症成功诱导。 UH组肠道结构病理损伤最为明显。 UH组血清和组织Hcy、血清内毒素和肠道通透性均显着升高。与NC、H、U组相比，UH组claudin-1、occludin、ZO-1蛋白含量均有不同程度降低，血清和组织中IL-6、TNF-α、MDA含量显着升高，SOD活性显着降低。补充益生菌 VSL#3 不同程度地改善了这些参数，并上调了紧密连接蛋白的丰度，这表明 Hcy 在尿毒症患者肠道通透性增加和上皮屏障破坏中发挥着作用。结论：Hcy通过刺激炎症和氧化损伤，加重肠道通透性增加和上皮屏障破坏。服用益生菌可以通过降低 Hcy 诱导的炎症和氧化水平来减轻这种损害。
Background/Aims: Previous studies have shown that homocysteine (Hcy) is an important intestinal-derived uremic toxin. However, whether Hcy is involved in the epithelial barrier dysfunction observed in uremia remains unclear. This study aimed to investigate the effect of Hcy on intestinal permeability and intestinal barrier structure and function in adenine-induced uremic rats. Methods: Sprague-Dawley rats were divided into five groups: normal control (group NC), Hcy (group H), uremia (group U), uremia + Hcy (group UH), and uremia + Hcy + VSL#3 (group UHV). Experimental uremia was induced by intragastric adenine administration, and Hcy was injected subcutaneously. The animal models were assessed for renal function and pathological tissue staining. The pathological changes of intestinal tissue were observed by hematoxylin and eosin staining and electron microscopy. The serum and intestinal tissue levels of Hcy, interleukin (IL)-6, tumor necrosis factor (TNF)-α, superoxide dismutase (SOD), and malondialdehyde (MDA) as well as serum endotoxin and intestinal permeability were assessed. The levels of the tight junction proteins claudin-1, occludin, and zonula occludens-1 (ZO-1) were assessed by western blotting. Results: Blood analyses and renal pathology indicated that experimental uremia was induced successfully. Pathological damage to intestinal structure was most obvious in group UH. Serum and tissue Hcy, serum endotoxin, and intestinal permeability were significantly elevated in group UH. The protein levels of claudin-1, occludin, and ZO-1 were decreased to various degrees in group UH compared with groups NC, H, and U. The serum and tissue levels of IL-6, TNF-α, and MDA were significantly increased, while SOD activity was markedly decreased. Supplementation with the probiotic VSL#3 improved these parameters to various degrees and up-regulated the abundance of tight junction proteins, which indicated a role for Hcy in the increase of intestinal permeability and destruction of the epithelial barrier in uremia. Conclusion: Hcy aggravates the increase of intestinal permeability and destruction of the epithelial barrier by stimulating inflammatory and oxidative damage. Probiotic administration can ameliorate this damage by reducing the levels of Hcy-induced inflammation and oxidation.