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The functional analysis of cell polarity protein aPKCI. in glomerular podocytes

细胞极性蛋白aPKCI的功能分析。

基本信息

批准号：
18590304
负责人：
HIROSE Tomonori
金额：
$ 1.62万
依托单位：
Yokohama City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590304/
关键词：
glomerular disease kidney disease animal models of disease cell polarity signal transduction 分子病態学

项目摘要

We originally established a mouse model of glomerular disease by podocyte-specific deletion of aPKClambda. Clinical and histopathological examinations of blood, urine, and kidneys of these mice confirmed that they develop dysfunctions of the slit diaphragm with proteinuria, glomerulosclerosis, and renal failure. These results indicate that our mice can serve as a useful model to analyze glomerular diseases. We extended these results to reveal molecular mechanisms of glomerular diseases and obtained the following results.1. The electron microscopic analyses of our model mice in various stages revealed a step-wise progression of defects in the slit diaphragms. Although the slit diaphragms were formed at first, they were dislocated, disorganized, and lost along with the growth of mice. The glomerular basement membranes were not significantly affected.2. To clarify the function of aPKC in the regulation of glomerular functions, we examined the functional interactions between aPKC and the structural proteins in slit diaphragms: nephrin and podocin. We fund that a specific inhibitor for aPKC significantly disturbed the distribution of nephrin and podocin in the isolated rat glomeruli. However, the formation of nephrin-podocin complex was not significantly affected by aPKC inhibitor.These data indicate that aPKC is required for the proper distribution of the structural proteins in slit diaphragms. It is also suggested that the functional disturbance in aPKC can be involved in the development of glomerular diseases.Along with above observations, we revealed that aPKC regulates the restriction of a specific lipid to determine the basolateral domains and that aPKC-binding protein PAR3 plays a critical role in the establishment of apical domains.We published and reported these results as indicated in the section 11.

我们最初通过足细胞特异性缺失aPKClambda建立了肾小球疾病的小鼠模型。对这些小鼠的血液、尿液和肾脏的临床和组织病理学检查证实，它们出现了裂隙隔功能障碍，并伴有蛋白尿、肾小球硬化和肾功能衰竭。这些结果表明，我们的小鼠可以作为分析肾小球疾病的有用模型。我们将这些结果扩展到揭示肾小球疾病的分子机制，并获得了以下结果。我们的模型小鼠在不同阶段的电子显微镜分析显示，裂隙横隔膜的缺陷是逐步发展的。虽然最初形成了裂隙横隔膜，但随着小鼠的生长发育，裂隙横隔膜错位、紊乱和丢失。结论：1.肾小球基底膜未受明显影响。为了阐明aPKC在肾小球功能调节中的作用，我们研究了aPKC与裂隙隔膜结构蛋白neaffin和podocin之间的功能相互作用。我们发现，aPKC的特异性抑制剂显著干扰了neparin和podocin在分离的大鼠肾小球中的分布。然而，aPKC抑制剂并不显著影响neparin-podocin复合体的形成。这些数据表明，aPKC是结构蛋白在裂隙隔膜中正确分布所必需的。此外，我们还发现，aPKC的功能紊乱可能参与了肾小球疾病的发展。根据以上观察，我们揭示了aPKC调节特定脂类的限制以确定基侧结构域，并且aPKC结合蛋白PAR3在顶区的建立中起着关键作用。