Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury.
Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury.
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Rho GTPases Rac1和Cdc42在足细胞损伤中的发散功能。
DOI：
10.1038/ki.2013.175
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发表时间：
2013-11
影响因子：
19.6
通讯作者：
中科院分区：
文献类型：
--
作者：
足细胞是高度特化的上皮细胞，具有复杂的肌动蛋白细胞骨架结构，对维持肾小球滤过屏障至关重要。哺乳动物Rho GTP酶Rac 1和Cdc 42是控制许多细胞过程的分子开关，但最为人所知的是它们在调节肌动蛋白细胞骨架动力学中的作用。在这里，我们采用足细胞特异性Cre-lox技术，发现Rac 1缺失的小鼠在成年后表现出正常的足细胞形态，没有肾小球功能障碍。使用急性足细胞损伤的硫酸鱼精蛋白模型，足细胞特异性Rac 1缺失防止足突消失。然而，在慢性高血压肾小球损伤的长期模型中，Rac 1的缺失导致白蛋白尿和肾小球硬化的加重。相反，足细胞特异性缺失Cdc 42的小鼠早在10日龄就出现严重的蛋白尿、足细胞足突消失和肾小球硬化。此外，裂隙隔膜蛋白nephrin和podocin被重新分布，并且cofilin被去磷酸化。Cdc 42是维持足细胞结构和功能所必需的，而Rac 1在生理稳态下完全失活。然而，Rac 1具有有益或有害的作用，这取决于足细胞损伤的背景。因此，我们的研究强调了Rac 1和Cdc 42功能在足细胞维持和损伤中的不同作用。
Podocytes are highly specialized epithelial cells with complex actin cytoskeletal architecture crucial for maintenance of the glomerular filtration barrier. The mammalian Rho GTPases Rac1 and Cdc42 are molecular switches that control many cellular processes, but are best known for their roles in the regulation of actin cytoskeleton dynamics. Here we employed podocyte-specific Cre-lox technology and found that mice with deletion of Rac1 display normal podocyte morphology without glomerular dysfunction well into adulthood. Using the protamine sulfate model of acute podocyte injury, podocyte-specific deletion of Rac1 prevented foot process effacement. In a long-term model of chronic hypertensive glomerular damage, however, loss of Rac1 led to an exacerbation of albuminuria and glomerulosclerosis. In contrast, mice with podocyte-specific deletion of Cdc42 had severe proteinuria, podocyte foot process effacement, and glomerulosclerosis beginning as early as 10 days of age. In addition, slit diaphragm proteins nephrin and podocin were redistributed and cofilin was de-phosphorylated. Cdc42 is necessary for the maintenance of podocyte structure and function, but Rac1 is entirely dispensable in physiologic steady state. However, Rac1 has either beneficial or deleterious effects depending on the context of podocyte impairment. Thus, our study highlights the divergent roles of Rac1 and Cdc42 function in podocyte maintenance and injury.
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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：
3.7
作者：
Hirose, Tomonori;Satoh, Daisuke;Ohno, Shigeo
通讯作者：
Ohno, Shigeo
DOI：
10.1073/pnas.0603533103
发表时间：
2006-10-31
影响因子：
11.1
作者：
Chen, Lei;Liao, Guanghong;Zheng, Yi
通讯作者：
Zheng, Yi
影响因子：
4.7
作者：
Hsu, Hsiang-Hao;Hoffmann, Sigrid;Pavenstaedt, Hermann
通讯作者：
Pavenstaedt, Hermann
影响因子：
4.8
作者：
Corbetta, Sara;Gualdoni, Sara;de Curtis, Ivan
通讯作者：
de Curtis, Ivan