Regulation of bile canalicular barrier by a novel tight junction protein claudin-2 during cholestasis

胆汁淤积期间新型紧密连接蛋白claudin-2对胆管屏障的调节

• 批准号: 17590308
• 负责人: KOJIMA Takashi
• 金额: $ 2.3万
• 依托单位: Sapporo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590308/
• 关键词: cholestasis; hepatocyte; tight junction; claudin-2; oncostatin M; hepatic cell polarity; bile canaliculi formation

Hepatic tight junctions (TJs) play crucial roles in the barrier to keep bile in bile canaliculi away from the blood circulation, which we call the bloc d-billiary-barrier. Intrahepatic cholestasis or impairment of bile flow is an important manifestation of inherited and acquired liver disease. In rodent livers, integral TJ proteins claudin-1,-2,-3,-5 and-14 are detected. CLaudin-2 shows a lobular gradient increasing from periportal to pericentral hepatocytes, whereas claudin-1 and-3 are expressed in the whole liver lobule. Although claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells, the physiological functions and regulation of claudin-2 in hepatocytes remain unclear. Oncostatin M (OSM) is a multifunctional cytokine implicated in the differentiation c f hepatocytes that induces formation of E-cadherin-based adherens junctions in fetal hepatocytes. In this study, we examined whether OSM could induce expression and function of claudin-2 in roden … More t hepatocytes, immortalized mouse and primary cultured proliferative rat hepatocytes. In the immortalized mouse and primary cultured proliferative rat hepatocytes, treatment with OSM markedly increased mRNA and protein of claudin-2 together with formation of developed networks of TJ strands. The increase of claudin-2 enhanced the paracellular barrier function which depended on molecular size. The increase of claudin-2 expression induced by OSM in rodent hepatocytes was regulated through distinct signaling pathways including PKC. Furthermore, we examined effects of claudin-2 on bile canaliculi formation using WIF-B9 hepatic cells which has hepatic cell polarity. In treatment with phenobarbital, bile canaliculi formation was induced and dilated together with an increase of claudin-2 expression. In treatment with siRNA of claudin-2, the bile canaliculi formation was inhibited by downregulation of claudin-2. These results suggest that expression of claudin-2 in hepatocytes may play a specific role as controlling the size of paracellular permeability in the barrier to keep bile in bile canaliculi and bile canaliculi formation. Less

肝紧密连接（TJs）是胆管内胆汁远离血液循环的屏障，我们称之为阻塞性胆汁屏障（blockd-billiary-barrier）。肝内胆汁淤积或胆汁流动受损是遗传性和获得性肝病的重要表现。在啮齿动物肝脏中，检测到完整的TJ蛋白claudin-1、claudin-2、claudin-3、claudin-5和claudin-14。CLaudin-2显示从门静脉周围到中央周围肝细胞的小叶梯度增加，而claudin-1和-3在整个肝小叶中表达。虽然claudin-2的表达诱导上皮细胞紧密连接中的阳离子选择性通道，但claudin-2在肝细胞中的生理功能和调节仍不清楚。抑瘤素M（Oncostatin M，OSM）是一种多功能细胞因子，参与肝细胞的分化，诱导胎肝细胞中基于E-钙粘蛋白的粘附连接的形成。在本研究中，我们检测了OSM是否可以诱导罗登Claudin-2的表达和功能 ...更多信息 t肝细胞、永生化小鼠和原代培养的增殖性大鼠肝细胞。在永生化的小鼠和原代培养的增殖性大鼠肝细胞中，用OSM处理显著增加了紧密连接蛋白-2的mRNA和蛋白，同时形成了发达的TJ链网络。claudin-2的增加增强了依赖于分子大小的细胞旁屏障功能。在啮齿动物肝细胞中，OSM诱导的claudin-2表达的增加通过包括PKC在内的不同信号通路来调节。此外，我们使用具有肝细胞极性的WIF-B 9肝细胞检测了claudin-2对胆小管形成的影响。在苯巴比妥的治疗中，胆小管的形成被诱导和扩张，同时增加claudin-2的表达。在用claudin-2的siRNA处理中，通过下调claudin-2来抑制胆小管形成。这些结果表明，在肝细胞中表达的claudin-2可能发挥特定的作用，作为控制的大小的细胞旁通透性的屏障，以保持胆汁在胆小管和胆小管的形成。少

项目成果

Glial cell-derived cytokines attenuate the breakdown of vascular integrity in diabetic retinopathy

• DOI: 10.2337/db06-1431
• 发表时间: 2007-05-01
• 期刊: DIABETES
• 影响因子: 7.7
• 作者: Nishikiori, Nami;Osanai, Makoto;Sawada, Norimasa
• 通讯作者: Sawada, Norimasa

Activation of p21 CIP1/WAF1 gene expression and inhibition of cell proliferation by overexpression of hepatocyte nuclear factor-4α

• DOI: 10.1016/j.yexcr.2004.08.014
• 发表时间: 2005-01-01
• 期刊: EXPERIMENTAL CELL RESEARCH
• 影响因子: 3.7
• 作者: Chiba, H;Itoh, T;Sawada, N
• 通讯作者: Sawada, N

Connexin 26 expression prevents down-regulation of barrier and fence functions of tight junctions by Na+/K+-ATPase inhibitor ouabain in human airway epithelial cell line Calu-3

• DOI: 10.1016/j.yexcr.2006.08.014
• 发表时间: 2006-11-15
• 期刊: EXPERIMENTAL CELL RESEARCH
• 影响因子: 3.7
• 作者: Go, Mitsuru;Kojima, Takashi;Sawada, Norimasa
• 通讯作者: Sawada, Norimasa

Cellular networks of human tymic medullary dtromas coordinated by p53-related transcription factors.

由 p53 相关转录因子协调的人胸腺髓质细胞网络。

• 发表时间: 2006
• 期刊: J Histochem Cytochem 54
• 作者: Ichimiya;S;et. al.
• 通讯作者: et. al.

胸腺ストローマをつなぐタイト結合

连接胸腺基质的紧密连接

• 发表时间: 2006
• 作者: 一宮 慎吾;他
• 通讯作者: 他