Itoh Masahiko, Nakadate Kazuhiko, Horibata Yasuhiro, Matsusaka Taiji, Xu Jianliang, Hunziker Walter, Sugimoto Hiroyuki
Department of Biochemistry, School of Medicine, Dokkyo Medical University, Mibu-machi, Shimotsuga-gun, Tochigi, Japan.
Department of Basic Biology, Educational and Research Center for Pharmacy, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan.
PLoS One. 2014 Sep 3;9(9):e106621. doi: 10.1371/journal.pone.0106621. eCollection 2014.
Blood filtration in the kidney glomerulus is essential for physiological homeostasis. The filtration apparatus of the kidney glomerulus is composed of three distinct components: the fenestrated endothelial cells, the glomerular basement membrane, and interdigitating foot processes of podocytes that form the slit diaphragm. Recent studies have demonstrated that podocytes play a crucial role in blood filtration and in the pathogenesis of proteinuria and glomerular sclerosis; however, the molecular mechanisms that organize the podocyte filtration barrier are not fully understood. In this study, we suggest that tight junction protein 1 (Tjp1 or ZO-1), which is encoded by Tjp1 gene, plays an essential role in establishing the podocyte filtration barrier. The podocyte-specific deletion of Tjp1 down-regulated the expression of podocyte membrane proteins, impaired the interdigitation of the foot processes and the formation of the slit diaphragm, resulting in glomerular dysfunction. We found the possibility that podocyte filtration barrier requires the integration of two independent units, the pre-existing epithelial junction components and the newly synthesized podocyte-specific components, at the final stage in glomerular morphogenesis, for which Tjp1 is indispensable. Together with previous findings that Tjp1 expression was decreased in glomerular diseases in human and animal models, our results indicate that the suppression of Tjp1 could directly aggravate glomerular disorders, highlights Tjp1 as a potential therapeutic target.
肾小球的血液滤过对于生理稳态至关重要。肾小球的滤过装置由三个不同的部分组成：有窗孔的内皮细胞、肾小球基底膜以及形成裂孔隔膜的足细胞的指状突起。最近的研究表明，足细胞在血液滤过以及蛋白尿和肾小球硬化的发病机制中起关键作用；然而，组织足细胞滤过屏障的分子机制尚未完全了解。在本研究中，我们认为由Tjp1基因编码的紧密连接蛋白1（Tjp1或ZO-1）在建立足细胞滤过屏障中起重要作用。Tjp1在足细胞中的特异性缺失下调了足细胞膜蛋白的表达，损害了足突的指状交叉和裂孔隔膜的形成，导致肾小球功能障碍。我们发现，在肾小球形态发生的最后阶段，足细胞滤过屏障可能需要整合两个独立的单元，即预先存在的上皮连接成分和新合成的足细胞特异性成分，而Tjp1对此不可或缺。结合之前在人类和动物模型的肾小球疾病中Tjp1表达降低的研究结果，我们的结果表明，Tjp1的抑制可直接加重肾小球疾病，突出了Tjp1作为潜在治疗靶点的地位。
