An Essential Role of the Universal Polarity Protein, aPKCλ, on the Maintenance of Podocyte Slit Diaphragms
An Essential Role of the Universal Polarity Protein, aPKCλ, on the Maintenance of Podocyte Slit Diaphragms
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DOI：
10.1371/journal.pone.0004194
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发表时间：
2009-01-14
期刊：
影响因子：
3.7
通讯作者：
Ohno, Shigeo
中科院分区：
文献类型：
--
作者：
Hirose, Tomonori;Satoh, Daisuke;Ohno, Shigeo
肾小球内脏上皮细胞（足细胞）含有交错突起，形成专门的细胞间连接，称为狭缝隔膜，在肾小球中提供选择性过滤屏障。对家族性肾病综合征致病突变和小鼠靶向诱变的分析揭示了几种蛋白质在狭缝隔膜组装中的关键作用。肾蛋白-足蛋白复合物是狭缝隔膜的主要成分。然而，调节这些蛋白质以维持狭缝隔膜的分子机制仍然是未知的。在这里，我们证明了PAR 3-非典型蛋白激酶C（aPKC）-PAR 6 β细胞极性蛋白与nephrin共定位于狭缝隔膜。此外，小鼠足细胞中aPKC λ的选择性耗竭导致裂孔隔膜的解体、顶-基底细胞极性的紊乱和局灶节段性肾小球硬化（FSGS）。aPKC-PAR 3复合物通过PAR 3和nephrin之间的直接相互作用与足细胞中的nephrin-podocin复合物缔合，并且aPKC的激酶活性是nephrin和podocin在足细胞中的适当分布所需的。这些观察结果不仅建立了一个关键的功能，极性蛋白质在维持狭缝隔膜，但也意味着他们的潜在参与FSGS肾功能衰竭。
Glomerular visceral epithelial cells (podocytes) contain interdigitated processes that form specialized intercellular junctions, termed slit diaphragms, which provide a selective filtration barrier in the renal glomerulus. Analyses of disease-causing mutations in familial nephrotic syndromes and targeted mutagenesis in mice have revealed critical roles of several proteins in the assembly of slit diaphragms. The nephrin-podocin complex is the main constituent of slit diaphragms. However, the molecular mechanisms regulating these proteins to maintain the slit diaphragms are still largely unknown. Here, we demonstrate that the PAR3-atypical protein kinase C (aPKC) -PAR6 beta cell polarity proteins co-localize to the slit diaphragms with nephrin. Furthermore, selective depletion of aPKC lambda in mouse podocytes results in the disassembly of slit diaphragms, a disturbance in apico-basal cell polarity, and focal segmental glomerulosclerosis (FSGS). The aPKC-PAR3 complex associates with the nephrin-podocin complex in podocytes through direct interaction between PAR3 and nephrin, and the kinase activity of aPKC is required for the appropriate distribution of nephrin and podocin in podocytes. These observations not only establish a critical function of the polarity proteins in the maintenance of slit diaphragms, but also imply their potential involvement in renal failure in FSGS.