Claudin-18: a dominant tight junction protein in Barrett's esophagus and likely contributor to its acid resistance
Claudin-18: a dominant tight junction protein in Barrett's esophagus and likely contributor to its acid resistance
复制标题
DOI：
10.1152/ajpgi.00158.2007
复制
发表时间：
2007-12-01
影响因子：
4.5
通讯作者：
Orlando, Roy C.
中科院分区：
文献类型：
--
作者：
Jovov, Biljana;Van Itallie, Christina M.;Orlando, Roy C.
巴雷特食管 (BE) 是一种特殊的柱状上皮 (SCE)，可替代患有反流病的受试者中受损的鳞状上皮 (SqE)，因此它显然比 SqE 更耐酸。人们对 SCE 如何抵抗酸损伤知之甚少；一种方法可能涉及改变紧密连接 (TJ)，因为 SqE 中的 TJ 是反流病中酸攻击和损害的早期目标。为了评估这种可能性，对 BE SCE 的内窥镜活检和来自无食管疾病受试者的健康 SqE 的内窥镜活检进行了 21 种紧密蛋白的定量 RT-PCR。在 SCE 中，Cldn-18 在 mRNA 水平上表达最高，这一发现与免疫印迹上蛋白质表达的显着升高相一致。相比之下，在 SqE 中，Cldn-18 在 mRNA 水平上表达最低，在蛋白质水平上检测不到。免疫荧光研究显示 Cldn-18 的膜定位以及与紧密连接蛋白 zonula occlusionns-1 的共定位。当 Cldn-18 在 MDCK II 细胞中过表达并以单层形式安装在 Ussing 室中时，它会提高电阻，并且与亲代 MDCK 细胞相比，它会升高电阻，如 NaCl 梯度的稀释电位较低和酸性梯度的扩散电位较低所示，选择性地降低了对 Na+ 和 H+ 的细胞旁通透性。我们得出结论，Cldn-18 是 SCE TJ 中的主要紧密蛋白，并提出从 SqE 中缺乏 Cldn-18 的 TJ 到 SCE 中富含 Cldn-18 的 TJ 的变化有助于 BE 具有更强的耐酸性。
Barrett's esophagus (BE) is a specialized columnar epithelium (SCE) that develops as replacement for damaged squamous epithelium (SqE) in subjects with reflux disease, and as such it is apparently more acid resistant than SqE. How SCE resists acid injury is poorly understood; one means may involve altered tight junctions (TJs) since the TJ in SqE is an early target of attack and damage by acid in reflux disease. To assess this possibility, quantitative RT-PCR for 21 claudins was performed on endoscopic biopsies on SCE of BE and from healthy SqE from subjects without esophageal disease. In SCE, Cldn-18 was the most highly expressed at the mRNA level and this finding is paralleled by marked elevation in protein expression on immunoblots. In contrast in SqE, Cldn-18 was minimally expressed at the mRNA level and undetectable at the protein level. Immunofluorescence studies showed membrane localization of Cldn-18 and colocalization with the tight junction protein, zonula occludens-1. When Cldn-18 was overexpressed in MDCK II cells and mounted as monolayers in Ussing chambers, it raised electrical resistance and, as shown by lower dilution potentials to a NaCl gradient and lower diffusion potentials to acidic gradients, selectively reduced paracellular permeability to both Na+ and H+ compared with parental MDCK cells. We conclude that Cldn-18 is the dominant claudin in the TJ of SCE and propose that the change from a Cldn-18-deficient TJ in SqE to a Cldn-18-rich TJ in SCE contributes to the greater acid resistance of BE.