Synaptopodin protects against proteinuria by disrupting Cdc42:IRSp53:Mena signaling complexes in kidney podocytes.
Synaptopodin protects against proteinuria by disrupting Cdc42:IRSp53:Mena signaling complexes in kidney podocytes.
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DOI：
10.2353/ajpath.2007.070075
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发表时间：
2007-08
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通讯作者：
Etsuko Yanagida-Asanuma;K. Asanuma;Kwanghee Kim;M. Donnelly;Hoon Young Choi;Jae Hyung Chang;S. Suetsugu;Y. Tomino;T. Takenawa;C. Faul;P. Mundel
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作者：
Etsuko Yanagida-Asanuma;K. Asanuma;Kwanghee Kim;M. Donnelly;Hoon Young Choi;Jae Hyung Chang;S. Suetsugu;Y. Tomino;T. Takenawa;C. Faul;P. Mundel
肾脏足细胞的肌动蛋白基足突和插入的狭缝隔膜形成蛋白尿的最终屏障。影响几种足细胞蛋白的突变导致过滤屏障的破坏和高度动态的足细胞肌动蛋白细胞骨架的重排。因此，调节足细胞肌动蛋白细胞骨架可塑性的蛋白质对于维持肾屏障功能至关重要。Synaptopodin是一种肌动蛋白相关蛋白，对足细胞肌动蛋白细胞骨架的完整性至关重要，因为synaptopodin缺陷小鼠显示从硫酸鱼精蛋白诱导的足突消失和脂多糖诱导的肾病综合征中恢复受损。此外，synaptopodin和CD 2AP的双基因杂合性足以诱导小鼠自发性蛋白尿和局灶节段性肾小球硬化样肾小球损伤。在机制上，突触足蛋白通过阻断RhoA的蛋白酶体降解来诱导应力纤维。在这里，我们表明，synaptopodin直接结合到IRSp 53和抑制Cdc 42：IRSp 53：Mena启动的丝状伪足的形成，通过阻断Cdc 42和Mena的IRSp 53的结合。Mena抑制剂FP（4）-Mito抑制突触足蛋白敲除足细胞中异常丝状伪足的形成，并且当递送到小鼠中时防止脂多糖诱导的蛋白尿。synaptopodin作为Cdc 42：IRSp 53：Mena信号传导抑制剂的鉴定定义了一种新型抗蛋白尿信号传导途径，并为抗蛋白尿治疗方式的开发提供了新的靶点。
The actin-based foot processes of kidney podocytes and the interposed slit diaphragm form the final barrier to proteinuria. Mutations affecting several podocyte proteins cause disruption of the filtration barrier and rearrangement of the highly dynamic podocyte actin cytoskeleton. Proteins regulating the plasticity of the podocyte actin cytoskeleton are therefore of critical importance for sustained kidney barrier function. Synaptopodin is an actin-associated protein essential for the integrity of the podocyte actin cytoskeleton because synaptopodin-deficient mice display impaired recovery from protamine sulfate-induced foot process effacement and lipopolysaccharide-induced nephrotic syndrome. Moreover, bigenic heterozygosity for synaptopodin and CD2AP is sufficient to induce spontaneous proteinuria and focal segmental glomerulosclerosis-like glomerular damage in mice. Mechanistically, synaptopodin induces stress fibers by blocking the proteasomal degradation of RhoA. Here we show that synaptopodin directly binds to IRSp53 and suppresses Cdc42:IRSp53:Mena-initiated filopodia formation by blocking the binding of Cdc42 and Mena to IRSp53. The Mena inhibitor FP(4)-Mito suppresses aberrant filopodia formation in synaptopodin knockdown podocytes, and when delivered into mice protects against lipopolysaccharide-induced proteinuria. The identification of synaptopodin as an inhibitor of Cdc42:IRSp53:Mena signaling defines a novel antiproteinuric signaling pathway and offers new targets for the development of antiproteinuric therapeutic modalities.