aPKCλ maintains the integrity of the glomerular slit diaphragm through trafficking of nephrin to the cell surface.
aPKCλ maintains the integrity of the glomerular slit diaphragm through trafficking of nephrin to the cell surface.
复制标题
DOI：
10.1093/jb/mvu022
复制
发表时间：
2014-08
影响因子：
2.7
通讯作者：
Ohno S
中科院分区：
文献类型：
--
作者：
Satoh D;Hirose T;Harita Y;Daimon C;Harada T;Kurihara H;Yamashita A;Ohno S
肾小球足细胞是肾小球上皮细胞间的特异性细胞间连接，在肾小球中提供选择性滤过屏障。SD的功能障碍导致肾小球疾病，其特征在于SD组分如nephrin从细胞表面消失。虽然已经提出了SD组件的内吞和降解的重要性，SD的完整性的维护，完整的细胞表面SD组件的营业额的动态性质仍然不清楚。使用离体大鼠肾小球，我们表明，细胞表面SD组件的周转率相对较高，它们几乎完全消失，从细胞表面在几分钟内。异源表达的nephrin的胞吐作用而非胞吞作用需要细胞极性调节剂非典型蛋白激酶C（aPKC）的激酶活性。因此，我们证明足细胞特异性aPKCλ缺失导致SD组分的细胞表面定位减少，引起大量蛋白尿。总之，通过aPKC调节SD转换对于维持SD完整性至关重要，并且aPKC信号传导的缺陷可导致蛋白尿。这些发现不仅揭示了细胞表面SD成分的动态周转的关键重要性，而且还提出了一个新的肾小球疾病的病理生理基础。
The slit diaphragm (SD), the specialized intercellular junction between renal glomerular epithelial cells (podocytes), provides a selective-filtration barrier in renal glomeruli. Dysfunction of the SD results in glomerular diseases that are characterized by disappearance of SD components, such as nephrin, from the cell surface. Although the importance of endocytosis and degradation of SD components for the maintenance of SD integrity has been suggested, the dynamic nature of the turnover of intact cell-surface SD components remained unclear. Using isolated rat glomeruli we show that the turnover rates of cell-surface SD components are relatively high; they almost completely disappear from the cell surface within minutes. The exocytosis, but not endocytosis, of heterologously expressed nephrin requires the kinase activity of the cell polarity regulator atypical protein kinase C (aPKC). Consistently, we demonstrate that podocyte-specific deletion of aPKCλ resulted in a decrease of cell-surface localization of SD components, causing massive proteinuria. In conclusion, the regulation of SD turnover by aPKC is crucial for the maintenance of SD integrity and defects in aPKC signalling can lead to proteinuria. These findings not only reveal the pivotal importance of the dynamic turnover of cell-surface SD components but also suggest a novel pathophysiological basis in glomerular disease.
登录
查看更多内容
影响因子：
4
作者：
Lalli, Giovanna
通讯作者：
Lalli, Giovanna
影响因子：
13.6
作者：
Huber, Tobias B.;Hartleben, Bjoern;Schiffer, Mario
通讯作者：
Schiffer, Mario
影响因子：
21.3
作者：
Joffre, Carine;Barrow, Rachel;Kermorgant, Stephanie
通讯作者：
Kermorgant, Stephanie
影响因子：
3
作者：
Guan, N;Ding, J;Yang, JY
通讯作者：
Yang, JY
影响因子：
3.7
作者：
Hirose, Tomonori;Satoh, Daisuke;Ohno, Shigeo
通讯作者：
Ohno, Shigeo