Impaired enterocyte proliferation in aquaporin-3 deficiency in mouse models of colitis
Impaired enterocyte proliferation in aquaporin-3 deficiency in mouse models of colitis
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DOI：
10.1136/gut.2006.104620
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发表时间：
2007-11-01
期刊：
影响因子：
24.5
通讯作者：
Verkman, A. S.
中科院分区：
文献类型：
--
作者：
Thiagarajah, Jay R.;Zhao, Dan;Verkman, A. S.
背景/目的：最近的证据表明水通道蛋白（AQP）参与与跨上皮水转运无关的细胞功能。尽管 AQP 在胃肠道中表达，但其重要性迄今为止尚不清楚。 AQP3 是一种水/甘油转运蛋白，在结肠上皮细胞的基底外侧膜上表达。本研究的目的是利用炎症性肠病小鼠模型研究AQP3在肠上皮细胞增殖中的作用。方法：建立AQP3在小鼠结肠上皮中的表达和功能。通过口服硫酸葡聚糖或结肠内施用乙酸在野生型和AQP3缺失小鼠中诱导结肠炎。结果指标包括临床疾病严重程度、生存率、病理学和细胞反应。给一些小鼠注射甘油来测试是否可以改变疾病进展。结果：给予硫酸葡聚糖的AQP3缺失小鼠3天后出现严重结肠炎，伴有结肠出血、明显的上皮细胞丢失和死亡。通过细胞凋亡评估，野生型小鼠具有相当的初始结肠损伤，但其发展出的结肠炎严重程度明显较轻，存活时间>8天。 AQP3 缺失小鼠的细胞增殖大大减少。口服甘油显着提高了 AQP3 缺失小鼠的存活率并降低了结肠炎的严重程度。在乙酸模型中，AQP3 缺失小鼠的存活率也降低。结论：结果表明 AQP3 在肠上皮细胞增殖中发挥新作用，这可能与其甘油转运功能有关。因此，AQP3 是治疗与肠上皮细胞破坏相关的肠道疾病的潜在靶点。
Background/Aims: Recent evidence has implicated the involvement of aquaporins (AQPs) in cellular functions that are unrelated to transepithelial water transport. Although AQPs are expressed in the gastrointestinal tract, their importance has so far been unclear. AQP3 is a water/glycerol transporter expressed at the basolateral membrane of colonic epithelial cells. The aim of this study was to investigate the involvement of AQP3 in enterocyte proliferation using mouse models of inflammatory bowel disease.Methods: Expression and function of AQP3 in mouse colonic epithelium were established. Colitis was induced in wild-type and AQP3 null mice by oral dextran sulphate administration or intracolonic acetic acid administration. Outcome measures included clinical disease severity, survival, pathology and cellular responses. Some mice were administered glycerol to test whether disease progression could be altered.Results: AQP3 null mice given dextran sulphate developed severe colitis after 3 days, with colonic haemorrhage, marked epithelial cell loss and death. Wild-type mice, which had comparable initial colonic damage as assessed by cell apoptosis, developed remarkably less severe colitis, surviving to >8 days. Cell proliferation was greatly reduced in AQP3 null mice. Oral glycerol administration significantly improved survival and reduced the severity of colitis in AQP3 null mice. Survival was also reduced in AQP3 null mice in the acetic acid model.Conclusions: The results implicate a novel role for AQP3 in enterocyte proliferation that is probably related to its glycerol-transporting function. AQP3 is thus a potential target for therapy of intestinal diseases associated with enterocyte destruction.