Loss of Podocyte aPKCλ/ι Causes Polarity Defects and Nephrotic Syndrome
Loss of Podocyte aPKCλ/ι Causes Polarity Defects and Nephrotic Syndrome
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DOI：
10.1681/asn.2008080871
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发表时间：
2009-04-01
影响因子：
13.6
通讯作者：
Schiffer, Mario
中科院分区：
文献类型：
--
作者：
Huber, Tobias B.;Hartleben, Bjoern;Schiffer, Mario
非典型蛋白激酶 C (aPKC) 是进化上保守的 Par3-Par6-aPKC 复合体的核心成分，是细胞极性的基本调节因子之一。我们最近证明这些蛋白质与肾小球滤过屏障狭缝隔膜处的去氧肾上腺素分子相互作用。在这里，我们报道了小鼠足细胞特异性删除 aPKC lambda/iota 导致严重蛋白尿、肾病综合征以及出生后 4 至 5 周的死亡。基因敲除小鼠的足细胞足突出现结构缺陷，包括狭缝隔膜的错误定位。在肾小球中，aPKC lambda/iota 主要在发育中的肾小球上皮细胞和足细胞足突中表达。有趣的是，在生理条件下，aPKC lambda/iota 从发育中的足细胞的顶端表面易位到基底外侧，并且这种易位先于足突的发育和裂隙隔膜的形成。 aPKC lambda/iota 在维持裂隙隔膜和多细胞足突中发挥关键作用，aPKC lambda/iota 与 Neph-nephrin 裂隙隔膜复合物相关，并定位于丝状伪足的尖端和培养的足细胞的前缘。这些结果表明 aPKC 信号传导对于肾小球维持和发育至关重要。
Atypical protein kinase C (aPKC) is a central component of the evolutionarily conserved Par3-Par6- aPKC complex, one of the fundamental regulators of cell polarity. We recently demonstrated that these proteins interact with Neph-nephrin molecules at the slit diaphragm of the glomerular filtration barrier. Here, we report that podocyte-specific deletion of aPKC lambda/iota in mice results in severe proteinuria, nephrotic syndrome, and death at 4 to 5 wk after birth. Podocyte foot processes of knockout mice developed structural defects, including mislocalization of the slit diaphragm. In the glomerulus, aPKC lambda/iota was primarily expressed in developing glomerular epithelial cells and podocyte foot processes. Interestingly, under physiologic conditions, aPKC lambda/iota translocated from the apical surface to the basolateral side of developing podocytes, and this translocation preceded the development of foot processes and formation of slit diaphragms. Supporting a critical role for aPKC lambda/iota in the maintenance of slit diaphragms and poclocyte foot processes, aPKC lambda/iota associated with the Neph-nephrin slit diaphragm complex and localized to the tips of filopodia and leading edges of cultured podocytes. These results suggest that aPKC signaling is fundamental to glomerular maintenance and development.